Process for synthesis of axially chiral organoboron compounds

Abstract

The invention develops an efficient Rh catalyzed [2 + 2 + 2] cycloaddition for synthesizing the axial chiral aryl boron compound and having rotation resistance isomerization selectivity. The reaction of diyne and alkynyl boron occurs smoothly in an atom-economical manner, thereby producing a variety of C-B atropisomers in excellent yields and enantioselectivity. The scheme has the characteristics of mild conditions, wide substrate range and good functional tolerance. The obtained C-B atropisomer shows powerful synthesis application in the aspect of producing novel chiral phosphine ligands.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 511,224 filed on June 30, 2023, and the disclosure of the U.S. Provisional Patent Application is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to a method for synthesizing axial chiral compounds. More specifically, the present invention relates to a method for synthesizing axial chiral organoboron compounds. Background Art

[0003] As a special type of stereoisomerism, atropisomerism resulting from restricted rotation around a single bond represents a vital chiral element in nature. Axial chirality is abundantly present in countless natural products, drugs, and bioactive molecules. In addition, axial chiral frameworks have been used to develop advanced materials such as fluorescent sensors, chiral optical switches, and molecular machines. In addition, axial chiral scaffolds also constitute a variety of special chiral catalysts and ligands in asymmetric catalysis by taking advantage of their relatively rigid three-dimensional structure that creates an excellent environment for stereochemical control ( Figure 1A ). Due to its significance, the asymmetric structure of axially chiral compounds has become an interesting topic in synthetic chemistry.

[0004] To date, a variety of approaches have been developed to address this problem. Most of the established methods focus on the synthesis of CC biaryl atropisomers, which are classified according to different strategies, including asymmetric cross-coupling, enantioselective de novo formation of aromatics, dynamic kinetic resolution or desymmetrization of existing biaryls, center-to-axis chirality conversion, etc. In addition to CC biaryl atropisomers, atropisomers with a CX (X = heteroatom) axis have also emerged as novel axial chiral skeletons and have attracted extensive research interest in recent years. The introduction of heteroatoms on the stereo axis can provide new opportunities for the discovery of promising drugs, materials and chiral ligands by regulating their physical and chemical properties. In this context, significant progress has been made in the asymmetric preparation of CN atropisomers, while the development of synthetic methods for other types of CX (X≠N) atropisomers is still in its infancy. The lack of efficient synthetic tools also limits the exploration of these CX (X≠N) atropisomers in many fields ( Figure 1B ).

[0005] Boron is an important element in nature with unique characteristics. The incorporation of boron atoms into organic molecules has achieved remarkable results in organic synthesis, optoelectronic materials, and drug discovery. Therefore, the synthesis of chiral organoboron compounds has aroused great interest. 2Due to the planar structural properties of hybrid boron units, the vast majority of studies have focused on central chiral alkyl boron compounds, in which boron is directly or indirectly attached to an asymmetric tetrahedral carbon. However, axial chiral arylboron compounds with a CB stereo axis connecting two perpendicular planes are rarely explored. Compared with CC or CN axial chirality, due to the Csp 2 -B key (1.58A) than Csp 2 -Csp 2 Key (1.48A) and Csp 2 The longer bond length of the -N bond (1.44 Å) makes the construction of CB axial chirality more challenging, resulting in lower configurational stability and lower rotation barrier ( Figure 1B ).

[0006] Due to foreseeable challenges, only a few reports have been made public to date ( Figure 1C ). Although there are attempts including palladium-catalyzed atropisomer-selective Miyaura borylation to directly form the stereo-CB axis and desymmetrization strategies to construct CB axial chirality via CPA-catalyzed electrophilic aromatic substitution reactions, the development of novel synthetic methods that can generally access a variety of axially chiral arylboron compounds from simple starting materials remains highly sought after in the field. Summary of the invention

[0007] In view of the above needs, this article provides an improvement in the method for synthesizing axial chiral aromatic organoboron compounds by rhodium-catalyzed [2+2+2] cycloaddition atropisomerization, which is achieved by using readily available synthetic raw materials as reactants and mild synthetic conditions. The method also ensures stable yields and high enantioselectivity. Further, novel phosphine ligands can be synthesized from axial chiral aromatic organoboron compounds obtained as above.

[0008] In a first aspect of the present invention, there is provided a novel phosphine ligand represented by the following formula: Wherein R is selected from phenyl or cyclohexyl; wherein X is selected from N-toluenesulfonyl, wherein R1 is selected from substituted or unsubstituted (C 1-4 ) alkyl, benzyl Wherein R2 is selected from methyl or ethyl; wherein R3 is selected from substituted or unsubstituted (C 1-5 ) alkyl, substituted or unsubstituted (C 1-5 )alkenyl, phenyl or cyclopropane; and Where Y is selected from

[0009] In one embodiment of the first aspect of the present invention, the compound is represented by the following formula: Wherein R is selected from phenyl or cyclohexyl.

[0010] In another embodiment, a method for preparing the above compound is provided, the method comprising: An axially chiral aromatic organoboron compound represented by the following formula was prepared: wherein R1 is selected from substituted or unsubstituted (C 1-4 ) alkyl, benzyl, R2 is selected from methyl or ethyl; R3 is selected from substituted or unsubstituted (C 1-5 ) alkyl, substituted or unsubstituted (C 1-5 )alkenyl, phenyl or cyclopropane; and Y is selected from reacting the axial chiral organoboron compound with lithium bis(trimethylsilyl)amide (LiHDMS) in the presence of tetrahydrofuran at room temperature for 8-12 minutes to obtain an intermediate; and The intermediate is reacted with a phosphine chloride having the formula Cl-PR2, wherein R is selected from phenyl or cyclohexyl, at room temperature for 1 hour.

[0011] In further embodiments, the above methods have a yield of at least 70%.

[0012] In yet further embodiments, the compounds are obtained in an enantiomeric excess of at least 90%.

[0013] In a second aspect of the present invention, there is provided an improvement in a method for synthesizing an axially chiral aromatic organoboron compound, the improvement comprising reacting a boron-containing organic precursor material and a branched unsaturated linear organic precursor material in the presence of a rhodium catalyst and a chiral ligand.

[0014] In one embodiment of the second aspect of the present invention, the reacting the boron-containing organic precursor material and the branched unsaturated linear organic precursor material in the presence of a rhodium catalyst and a chiral ligand is carried out in an organic solvent at 55° C. to 65° C. for about 20 hours.

[0015] In another embodiment of the second aspect, the branched unsaturated linear organic precursor material is a diyne represented by the formula: Wherein R2 is selected from methyl or ethyl.

[0016] In other embodiments, the axially chiral aromatic organoboron compound is represented by the following formula: wherein R1 is selected from substituted or unsubstituted (C 1-4 ) alkyl, benzyl Wherein R2 is selected from methyl or ethyl; wherein R3 is selected from substituted or unsubstituted (C 1-5 ) alkyl, substituted or unsubstituted (C 1-5 )alkenyl, phenyl or cyclopropane; and Where Y is selected from

[0017] In yet another embodiment, the improved process has a yield of at least 50%.

[0018] In yet other embodiments, the enantiomeric excess of the axially chiral aromatic organoboron compound obtained from the improved process is at least 85%. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Embodiments of the present invention are described in more detail below with reference to the accompanying drawings, in which:

[0020] Figures 1A to 1D The significance of axial chiral chemistry and a strategy for the synthesis of CB atropisomers are demonstrated. Figure 1A Representative applications of atropisomers are shown. Figure 1B The challenges of CB atropisomer synthesis are shown. Figure 1C A previous strategy for the synthesis of CB atropisomers is shown. Figure 1D The strategy of the present invention for the synthesis of CB atropisomers: atropselective [2+2+2] cycloaddition is shown.

[0021] Figure 2A and 2B The preparation of alkynylboranes and the optimization of the [2+2+2] cycloaddition are shown. Figure 2A The preparation of alkynylboranes is shown. Figure 2B Optimization of the [2+2+2] cycloaddition is shown. Reaction conditions: The reaction was carried out with 1a (0.1 mmol), 2a (0.1 mmol), catalyst (5 mol%) and ligand (10 mol%) in solvent (1 mL) at the indicated temperature for 20 h. The isolated yields are provided and the ee was determined by chiral HPLC analysis. a L6 (5 mol%) was used. b 2a (0.15 mmol, 1.5 eq.) was used cRh(cod)2OTf(1mol%) and L6(1mol%) were used. d 1a (0.2 mmol) and 2a (0.3 mmol).

[0022] Figure 3 The substrate scope of the diyne is shown. Reaction conditions: The reaction was carried out with 1 (0.2 mmol), 2a (0.3 mmol), Rh(cod)2OTf (5 mol%) and L6 (5 mol%) in toluene (2 mL) at 60 °C for 20 h. The isolated yields are provided and the ee was determined by chiral HPLC analysis. Add dropwise a Diyne (0.2 mmol in 2 mL toluene) for 3 hours.

[0023] Figure 4A and 4B The substrate scope of alkynyl Bdan is shown. Reaction conditions: The reaction was carried out with 1 (0.2 mmol), 2 (0.3 mmol), Rh(cod)2OTf (5 mol%) and L6 (5 mol%) in toluene (2 mL) at 60°C for 20 hours. The isolated yields are provided and the ee is determined by chiral HPLC analysis. Figure 4A Variations in the alkyne substituents are shown. Figure 4B Variations of the Bdan substituents are shown.

[0024] Figure 5 The substrate scope of alkynyl Baam is shown. Reaction conditions: The reaction was carried out with 1 (0.2 mmol), 2 (0.3 mmol), Rh(cod)2OTf (5 mol%) and L6 (5 mol%) in toluene (2 mL) at 60°C for 20 hours. The isolated yields are provided and the ee is determined by chiral HPLC analysis.

[0025] Figures 6A to 6C The comprehensive utility of the developed method is shown. Fig. 6A Later modifications of the drug are shown; Figure 6B Gram-scale synthesis is shown; Figure 6C Basic functional group transformations on axial chiral arylboron scaffolds are shown. (a) X = Cl, NaSPh (2 eq.), DMF, room temperature, 2 hours. (b) X = OTs, NaI (2 eq.), acetone, 60°C, 24 hours. (c) HP(O)Ph2 (2 eq.), K2CO3 (2 eq.), TBAI (20 mol%), DMF, 70°C, 15 hours. (d) NaN3 (2 eq.), DMF, 60°C, 3 hours. (e) Phenylacetylene (2 eq.), CuSO4 (5 mol%), sodium ascorbate (20 mol%), tBuOH / H2O (1 / 1), 60°C, 15 hours.

[0026] Figures 7A to 7D The synthetic applications of the obtained CB atropisomers are shown. Fig. 7A The synthesis of tetra-ortho-substituted axially chiral arylboron compounds is shown. Electrophiles used: a MeI, b TMSCl, c BzCl, d Cl-PPh2, e Cl-PCy2, f Cl-P i Pr2. Figure 7B The construction of a library of novel chiral phosphine ligands is shown. Figure 7C The application of the newly synthesized chiral ligand in Pd-catalyzed asymmetric allylic alkylation is demonstrated. Fig.7D The intramolecular cyclization used to construct the bridged CB atropisomer is shown.

[0027] Figures 8A to 8C Mechanistic studies are shown. Fig. 8A Determination of the rotation barrier of 4a is shown. Figure 8B An experiment showing nonlinear effects is shown. Figure 8C The proposed reaction mechanism is shown.

[0028] Fig. 9 The preparation of asymmetrically substituted 1,8-diaminonaphthalene (dan) is demonstrated.

[0029] Fig.10 The preparation of asymmetrically substituted anthranilamides (aam) is demonstrated.

[0030] Fig.11A The preparation of alkynyl Bdan compounds from common terminal alkynes is demonstrated; Fig. 11B The preparation of alkynyl Bdan compounds from terminal alkynes bearing sensitive functional groups is demonstrated; and Fig. 11C The preparation of alkynyl Bdan compounds by Grignard reagent is demonstrated.

[0031] Fig. 12A The preparation of alkynyl Baam compounds from common terminal alkynes is demonstrated; and Fig. 12B The preparation of alkynyl Baam compounds from Grignard reagents is demonstrated.

[0032] Fig.13A Shown are six chiral MOP ligands used to synthesize exemplary axially chiral aromatic organoboron compounds. Fig. 13B A schematic diagram of the improved synthetic route of L6 is shown.

[0033] Fig.14 An overall schematic diagram of a series of rhodium-catalyzed [2+2+2] cycloaddition reactions of diynes 1 with stationary species 2a is shown.

[0034] Fig.15 Shown is the overall schematic diagram of the rhodium-catalyzed [2+2+2] cycloaddition reaction of the fixed species diyne 1 with a series of alkynyl Bdan 2a.

[0035] Fig.16 Shown is the overall schematic diagram of the rhodium-catalyzed [2+2+2] cycloaddition reaction of the fixed species diyne 1 with a series of alkynyl Baam 2.

[0036] Fig.17 Shown is a schematic demonstration of the application of rhodium-catalyzed [2+2+2] cycloaddition reaction in late-stage drug modification.

[0037] Fig.18 An overall schematic diagram of the synthesis of tetra-ortho-substituted axially chiral arylboron compounds is shown.

[0038] Fig.19 An overall schematic diagram of the synthesis of various chiral phosphine ligands from axially chiral arylboron compounds is shown.

[0039] Fig. 20 An overall schematic diagram of the synthesis of bridged CB atropisomers from axially chiral arylboron compounds is shown.

[0040] Fig.21 Shown is an overall schematic diagram of Pd-catalyzed asymmetric allylic alkylation further catalyzed by the novel chiral phosphine ligand provided by the present invention, as well as species of novel chiral phosphine ligands suitable for Pd-catalyzed asymmetric allylic alkylation.

[0041] Fig. 22 The overall schematic diagram of Pd-catalyzed asymmetric Suzuki coupling further catalyzed by the novel chiral phosphine ligand provided by the present invention is shown, as well as species of novel chiral phosphine ligands suitable for Pd-catalyzed asymmetric allylic alkylation. DETAILED DESCRIPTION

[0042] As discussed above, axial chirality has been fully exploited in multiple application areas, ranging from chiral sensors, material science (e.g., nonlinear optics and liquid crystals), chiral catalysis, and numerous molecular-level uses, to pharmaceutical and biomedical applications, where axial chirality plays a particularly important role because the biological activity of drugs is highly dependent on their stereochemistry.

[0043] On the other hand, boron incorporation into organic molecules has also received increasing attention due to its wide applications in organic synthesis, optoelectronics, and medicine; and although the construction of said boron is difficult due to configurational instability and rotational barriers, its axial chiral variants are also being explored.

[0044] Alkynes are readily available synthetic starting materials with a variety of reactivities. Recently, alkynes have also been used for the asymmetric construction of atropisomers. One of the representative examples is the transition metal-catalyzed atropisomer-selective [2+2+2] cycloaddition, which can efficiently generate atropisomers by forming aromatics de novo in an atom-economical manner. The method has successfully generated various CC and CN atropisomers. Inspired by this chemistry, the [2+2+2] cycloaddition between alkynylborane and diynes can be used to construct CB atropisomers ( Figure 1D ).

[0045] However, it is foreseeable that there will be some challenges to achieve this. First, in order to achieve CB axial chirality (sufficiently stable for separation), appropriate sterically bulky boron protecting groups are essential for this process. Therefore, it is necessary to develop efficient preparation methods for these specific assembly alkynyl boron substrates.

[0046] Second, both the alkynyl boron and the diyne should be internal alkynes to ensure the presence of at least three ortho groups in the product to lock the CB stereoaxis, while the reactivity may be weakened due to the huge steric hindrance caused by the formation of fully substituted arenes.

[0047] Third, when considering the low configurational stability of CB atropisomers, it is necessary to find a suitable combination of chiral ligands and transition metal catalysts to achieve good reactivity and enantioselectivity under mild conditions.

[0048] Herein, a practical and efficient method for the selective atrop-transfer synthesis of axially chiral arylboron compounds via a rhodium-catalyzed [2+2+2] cycloaddition is provided. Crucially, the use of chiral MOP ligands enables good reactivity and excellent enantioselectivity control under mild conditions. The reaction is characterized by a wide substrate range and good functional group tolerance, producing a variety of CB atrop-transfer isomers in excellent yields and enantiomeric control. Alkynyl boron substrates can be easily obtained from terminal alkynes, providing a general platform for a variety of syntheses from simple starting materials. In addition, the obtained axially chiral arylboron products can be used as valuable precursors for the direct generation of new chiral phosphine ligands, which have shown potential in asymmetric catalysis.

[0049] In the following description, as preferred examples, methods for synthesizing axial chiral organoboron compounds are listed, etc. It will be clear to those skilled in the art that modifications including additions and / or substitutions may be made without departing from the scope and spirit of the invention. Specific details may be omitted so as not to obscure the invention; however, this disclosure is written to enable those skilled in the art to practice the teachings herein without undue experimentation.

[0050] result

[0051] First, a general method for preparing alkynyl boron substrates was developed. After several experiments, it was found that a series of alkynyl boron compounds ( Figure 3 ). This protocol is simple and can be carried out in a one-pot process without the need to isolate any intermediates. Since terminal alkynes are widely available starting materials, this protocol allows the direct synthesis of alkynyl boron compounds with a wide range of substituents on the alkyne moiety, such as alkyl, alkenyl, and aryl groups. 1,8-Diaminonaphthalene (dan) or o-aminobenzamide (aam) can be used as effective boron protecting groups, and at least one substituent at the nitrogen atom is essential for generating axial chirality. Compared to the commonly studied alkynyl Bpin compounds that need to be separated by distillation and stored under nitrogen, these alkynyl Bdan and Baam compounds have lower Lewis acidicity and can be easily obtained by silica gel chromatography or recrystallization. In addition, these compounds are air-stable solids and are easy to handle.

[0052] Diyne 1a and 1-heptynyl Bdan 2a were selected as model substrates to examine the reaction ( Figure 3). Several chiral ligands were initially investigated using Rh(nbd)2BF4 as the catalyst. While the bisphosphine ligand and other monophosphine ligands were ineffective, the MOP ligand L1 promoted the reaction to produce the axially chiral arylboron product 3a with a yield of 15% and an ee of 9% (entry 1). Using L1 as the ligand, other Rh(I) and Ir(I) catalysts were explored (entries 1-4). Fortunately, Rh(cod)2OTf significantly improved the reactivity and enantioselectivity (entry 4). This result suggests that both the olefin ligand and the counterion of the catalyst have a significant effect on this reaction. The temperature and solvent parameters were then evaluated, and using toluene as the solvent, the reaction could proceed better at 60°C, producing 3a with a yield of 77% and 81% ee (entry 6). Considering that the ligand may be crucial to the reaction, other MOP ligands L2-L6 were studied (entries 7-11). While the addition of steric hindrance to the alkoxy substituent caused a sharp drop in enantioselectivity (entries 7 and 8), the use of a smaller hydroxyl group further improved the enantioselectivity to 96% ee with a satisfactory yield of 71% (entry 9). Further removal of the hydroxyl group resulted in poor enantiocontrol (entry 10), while the introduction of a p-methyl group to the phenyl moiety could slightly increase the yield to 76% while retaining high enantioselectivity (entry 11). With L6 as the ligand, additional parameters regarding the catalyst / ligand ratio and the equivalents of 2a were optimized (entries 12-15). While reducing the catalyst / ligand ratio from 1:2 to 1:1 did not affect the reaction efficiency and enantioselectivity (entry 12), increasing the equivalents of 2a could further improve the yield (entry 13). Notably, the loading of catalyst and ligand could be reduced to 1 mol% without now decreasing the yield and enantioselectivity (entry 14). Finally, when the reaction was carried out at a 0.2 mmol scale, the axially chiral arylborane 3a could be obtained in 90% isolated yield and 96% ee (entry 15).

[0053] With the optimized reaction conditions in place, the next step was to explore the substrate scope. We first evaluated various diynes with different alkyne termini and tethers ( Figure 3). Most of them can react smoothly with 2a to produce the corresponding axial chiral arylboron products (3a-o) in good yields and enantioselectivities. The changes in the alkyne termini show that the Me and Et termini can be well tolerated, thereby producing products 3a, 3b in excellent yields and enantioselectivities, while the Ph termini produce moderate enantioselectivities (3c), probably because its larger steric hindrance is not conducive to enantiomeric control in the enantiomeric determination step. A series of diynes with different tethers also performed well, providing products 3d-o in moderate to good yields and enantioselectivities. A variety of functional groups are compatible with the reaction conditions, including esters (3a-c, 3h), ketones (3d, 3i, 3j), ethers (3g, 3o), protected alcohols (3f) and nitriles (3e). The reaction of diynes containing both phenyl and ester substituents at the quaternary tether carbon will produce products 3h with central chirality and axial chirality. In this case, moderate non-stereoselectivities were observed, while the enantioselectivities of each pair of enantiomers were still good. Diynes derived from cyclic frameworks can also be used to obtain products 3i-k with spiro units in satisfactory yields and enantioselectivities. The reaction can also achieve the construction of polycyclic aromatic compounds, providing 3l with a CB axial chiral scaffold in moderate yields and enantioselectivities. Notably, nitrogen- or oxygen-tethered diynes are also applicable, providing the corresponding products 3m-o in moderate yields and excellent enantioselectivities. In the case of 3o, it was found that slow addition of the diyne can effectively suppress the self-dimerization of the diyne and further improve the yield without reducing the enantioselectivity. Finally, asymmetric diynes with two different alkyne ends (Me and Ph) were studied. The reaction worked well, producing a pair of positional isomers 3pa, 3pb in high yields but low position selectivity. It was observed that the major product 3pa had excellent enantioselectivity, while the minor product 3pb showed moderate enantioselectivity.

[0054] Next, the generality of this reaction was examined by employing a series of alkynyl Bdan compounds (Figure 4). A large number of alkynyl Bdan compounds with different alkyne substituents could be successfully applied to this protocol to produce the corresponding axially chiral arylboron products with high efficiency and good enantioselectivity ( Figure 4A, 4a-u). Structural variations of axially chiral arylboron scaffolds can be widely achieved due to the wide range of substrates and the ease of access to alkynylboron compounds from common terminal alkynes. Methyl-substituted alkynyl Bdans undergo smooth cycloaddition with several diynes to provide products 4a-c in good yields and enantioselectivities. Enantiomers of 4a can be easily prepared using (S)-L6 as a ligand (ent-4a). Primary alkyl groups with different chain lengths or substitution patterns can be introduced as alkyne substituents to afford products 4d-o in excellent yields and enantioselectivities. Functional groups such as alkyl chlorides (4h), silyl ethers (4i), sulfonates (4j-l), esters (4m), and silicon groups (4o) can be well tolerated. The use of alkynyl Bdans with a methoxy group at the propargyl position produces product 4o in high yield but with reduced enantioselectivity, which may be due to the coordination effect between the methoxy group and the rhodium catalyst. It is worth noting that the reaction efficiency and enantioselectivity are related to the steric environment of the alkyne substituent. The reaction also proceeded successfully when secondary alkyl-substituted alkynyl Bdans were used, producing products 4p-r in moderate yields and slightly reduced enantioselectivities. The larger steric hindrance of the alkyne substituent enhances the self-dimerization of the diyne and reduces the enantiocontrol in the enantiodetermination step. Alkynyl Bdan compounds produced from terminal 1,3-enynes or phenylacetylene are also effective substrates. According to speculation, product 4s with a sterically small styrene substituent was obtained in high yield and enantioselectivity, while products 4t, 4u with sterically large cyclohexyl or phenyl substituents were produced with moderate efficiency and enantiocontrol. The absolute configuration of 4j was clearly determined by X-ray crystallographic analysis, and the other aryl Bdan products were assigned by analogy.

[0055] In addition, alkynyl Bdan compounds with various Bdan substituents were studied ( Figure 4B ). The reaction can tolerate a variety of benzyl groups with different para-, meta- or ortho-substituents, producing the corresponding products 5a-j in quantitative yields and excellent enantioselectivity. Some active functional groups such as bromide (5e), ​​iodide (5f) and borate (5g) are compatible, providing promising opportunities for further transformation. Polycyclic aromatic substrates can also be applied to obtain products 5k and 5l in high yields and enantioselectivity. In addition, alkyl-substituted aryl Bdan products 5m and 5n can be effectively formed with excellent enantioselectivity by this scheme. The robustness of this method is further demonstrated by using substrates with additional unsaturated parts. Since the cycloaddition occurs only at the boron-activated alkyne part, perfect chemical selectivity is observed. In addition, products 5o-p are produced in high yields and enantioselectivity.

[0056] Encouraged by the broad scope of this method for generating axially chiral aryl Bdan scaffolds, it is desirable to apply this reaction to construct other types of axially chiral arylboron compounds. 2 Atomic composition), so the next step is to explore the construction of axially chiral aromatic Baam compounds. Previous research on aromatic Baam compounds has focused on transition metal-catalyzed cross-coupling reactions, but their axial chirality is still unprecedented. The reaction of alkynyl Baam compounds with diynes has successfully constructed a series of axially chiral aromatic Baam compounds ( Figure 5 The generality of the reaction was fully evaluated by variations in alkyne substituents, Baam substituents, and diynes. Various aryl Baam compounds (6a-i, 6l, 6m) can be synthesized in moderate to good yields and excellent enantioselectivities. Substrates with existing chiral centers are also compatible to produce the corresponding products 6j, 6k with satisfactory nonstereoselectivities. The absolute configuration of 6c was unambiguously determined by X-ray crystallographic analysis, and the other aryl Baam products were assigned by analogy.

[0057] Several studies were performed to demonstrate the comprehensive utility of this approach. First, the reaction can be used for late-stage modification of drugs to afford the corresponding axially chiral arylboron derivatives ( Fig. 6A , 7a, 7b). Secondly, the reaction can be carried out on a gram scale, using only 1% Rh(cod)2OTf and 1% L6 under otherwise identical conditions to produce 4a or 4h in high yield and enantioselectivity ( Figure 6B ). It is worth noting that the excess alkynyl boron substrate can also be recovered after the reaction. Third, some basic functional group transformations were explored based on the axial chiral arylboron scaffolds 4h or 4k. Figure 6C As shown, alkyl chlorides were converted to alkyl sulfides (8a), while alkyl iodides (8b) were prepared from alkyl tosylates. The obtained alkyl iodides 8b were further subjected to nucleophilic substitution to produce alkyl phosphine oxides 8c and alkyl azides 8d. Afterwards, efficient click reactions were performed using 8d and phenylacetylene to produce triazoles 8e. Notably, all of these transformations could be efficiently achieved with a high degree of retention of enantiomeric purity.

[0058] Since a variety of axially chiral arylboron compounds were produced in the method developed in the present invention, the synthetic applications of these obtained atropisomers were further explored. First, all of the above-mentioned CB atropisomers obtained are tri-ortho-substituted scaffolds with an active NH bond on the Bdan or Baam moiety. Deprotonation of this NH bond can occur in the presence of LiHMDS as a base to generate a lithium amide intermediate that can be captured by a range of electrophilic reagents. Therefore, a variety of tetra-ortho-substituted axially chiral arylboron compounds can be formed. Fig. 7A As shown, the reaction of 4a with different electrophiles was studied. Methylation was achieved using iodomethane (9a), while assembly of the silyl group was accomplished by trimethylsilyl chloride (9b). Interestingly, when benzoyl chloride was used as the electrophile, benzoylation occurred only at the ortho-naphthalene site to form the tri-ortho-substituted product 9c. This unusual positional selectivity may benefit from the more stable six-membered ring transition state formed during the nucleophilic attack and the additional interaction between the lithium and the benzoyl oxygen. In addition, the reaction of 4a with different phosphine electrophiles can conveniently produce a series of chiral phosphine ligands 9d-f. Remarkably, all of these transformations exhibited high efficiency and excellent enantiomeric retention. Due to the importance of chiral phosphine ligands in asymmetric catalysis, the successful synthesis of 9d-f prompted the construction of a novel chiral phosphine ligand library from a variety of obtained axially chiral arylboron scaffolds ( Figure 7B ). The synthetic scheme is very general and can rapidly synthesize a variety of novel chiral phosphine ligands (9g-w) in good yields and high enantiomeric purity. Many functional groups including silicon groups (9g, 9h), alkyl chlorides (9k, 9l, 9v, 9w), silyl ethers (9m), sulfides (9n, 9o), phosphine oxides (9p) and olefins (9r, 9s) are well tolerated. Some chiral cooperative ligands such as phosphine sulfide ligands (9n, 9o), diphosphine monoxide ligands (9p) and phosphine-olefin ligands (9r, 9s) can also be prepared smoothly. Notably, the diphosphine monoxide ligand 9p can be further reduced to produce the chiral bisphosphine ligand 9x. With a library of novel chiral phosphine ligands, we evaluate the practicality of these chiral ligands in Pd-catalyzed asymmetric allylic alkylation ( Figure 7C). By using 9k as a ligand, the reaction of racemic 10a and 10b proceeded smoothly to produce product 10c in 99% yield and 45% ee, demonstrating the potential ability of these chiral ligands in asymmetric catalysis. Finally, when the axial chiral arylboron compounds 4j-l were treated with LiHMDS, intramolecular cyclization could occur to form bridged CB atropisomers 11a-c (Figure 7d). This is because the terminal alkyl tosylate can be regarded as an intramolecular electrophile, which can effectively capture the generated lithium amide intermediate. The configurational stability of these bridged CB atropisomers depends on the ring size. Although the six-membered ring 11a is configurationally unstable and racemization may occur at room temperature, the seven-membered ring 11b and the eight-membered ring 11c are sufficiently stable and can be separated with high enantiomeric purity. Although a large number of bridged atropisomers exist in biologically active natural products and drugs, existing synthetic methods mainly focus on bridged CC biaryls, while bridged CX atropisomers still lack effective synthetic methods.

[0059] Several studies have been performed. First, racemization experiments and DFT calculations were performed to examine the configurational stability of the obtained CB atropisomers, as exemplified by the determination of 4a ( Fig. 8A ). The racemization experiment was carried out by heating 4a in toluene at 100 °C. The rotation barrier of 4a was determined to be 32.8 kcal / mol, and the half-life at 100 °C was 192.5 h (8 days). DFT calculations were performed by rotational scanning of the CB bond, and the calculated rotation barrier was 34 kcal / mol. Compared with the previously reported CB atropisomers, the CB atropisomers obtained in this study have higher configurational stability. The fully substituted aromatic ring may increase the steric hindrance around the CB axis, resulting in a more stable configuration. Secondly, nonlinear effect experiments were performed to study the catalytically active species in this reaction. The reactions of 1a and 2b were carried out using a series of L6 with different ee, and the ee of 4a was determined by chiral HPLC analysis. As Figure 8B As shown, the ee of 4a is linearly related to the ee of L6, which indicates that the Rh / L6 ratio of the catalytically active species is 1 / 1. Finally, a reasonable reaction mechanism was proposed ( Figure 8C ). The reaction begins with an oxidative cyclometalation between the catalytically active species Rh(I) species A and the diyne 1 to generate the Rh(III) intermediate B. Then, B accepts the coordination of the alkynyl boron 2 to form a complex C. Afterwards, an enantioselective migration insertion occurs to obtain the raw intermediate D and produce axial chirality. In this step, the chiral ligand L6 can effectively distinguish the two ortho substituents on the boron group through steric hindrance, and make this process enantioselective. Finally, the enantiomer-retaining reduction elimination of D can obtain the axial chiral arylboron product 3 and regenerate A to achieve a catalytic cycle.

[0060] Examples

[0061] 1. A catalytic [2+2+2] cycloaddition atrop-selective construction of carbon-boron axial chirality

[0062] 1.1 General Information

[0063] All chemical reagents were purchased from Macklin, Aladdin, Bidepharm, Sigma-Aldrich and TCI. Solvents were purchased from Duksan, Labscan and Anaqua (Hong Kong). Anhydrous solvents were purchased from Acros and Alfa Aesar. All rhodium-catalyzed reactions were performed in oven-dried Schlenk tubes or flasks by standard Schlenk techniques under nitrogen atmosphere. Flash column chromatography was performed using silica gel (SiliCycle, SiliaFlash P60, 40-63 μm). Thin layer chromatography (TLC) was performed using silica gel plates (Merck silica gel 60F254). Compounds were visualized under UV light or by staining with an ethanol solution of phosphomolybdic acid. All NMR spectra were acquired on a Bruker 600 NMR spectrometer at 600 MHz ( 1 H NMR), 150MHz( 13 C NMR), 193MHz( 11 B NMR), 565MHz( 19 F NMR) and 243 MHz ( 31 Chemical shifts are reported in parts per million (ppm) and are for 1 H NMR, referenced to tetramethylsilane (0 ppm) or to 13 CNMR was referenced to CDCl3 (77 ppm). Coupling constants (J) are reported in Hertz (Hz). Abbreviations are given below: s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (sextet), m (multiplet), br (broad). 1 H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constant, number of protons). 13 CNMR, 11B NMR, 19 F NMR and 31 P NMR spectra are reported as chemical shifts. 13The carbon attached to boron is not usually observed in the C NMR spectrum. High-resolution mass spectra (HRMS) were recorded on an Agilent 6546 LC / Q-TOF spectrometer. Enantiomeric excess (ee) values ​​were determined by chiral HPLC (Agilent 1290 Infinity II) equipped with Daciel chiral columns (IA, IA-3, IB-3, IC-3, ID-3) using n-hexane and IPA as eluents. Dimethyl 2,2-di(but-2-yn-1-yl)malonate (1a) Dimethyl 2,2-di(pent-2-yn-1-yl)malonate (1b) Dimethyl 2,2-di(pent-2-yn-1-yl)malonate (1b) Dimethyl 2,2-bis(3-phenylprop-2-yn-1-yl)malonate (1c) 3,3-Di(but-2-yn-1-yl)pentane-2,4-dione (1d) 2,2-Di(but-2-yn-1-yl)malononitrile (1e) 6,6-Di(but-2-yn-1-yl)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disiloundecane (1f) 5,5-Bis(methoxymethyl)nona-2,7-diyne (1g) 2-(But-2-yn-1-yl)-2-phenylhex-4-ynoic acid methyl ester (1h) 2,2-Di(but-2-yn-1-yl)-5,5-dimethylcyclohexane-1,3-dione (1i) 2,2-Di(but-2-yn-1-yl)-1H-indene-1,3(2H)-dione (1j) 9,9-Di(but-2-yn-1-yl)-9H-fluorene (1k) 1,8-Di(prop-1-yn-1-yl)naphthalene(1l) N,N-Di(but-2-yn-1-yl)-4-methylbenzenesulfonamide (1m) 4-Bromo-N,N-di(but-2-yn-1-yl)benzenesulfonamide (1n) 1-(But-2-yn-1-yloxy)but-2-yn(1o) Dimethyl 2-(but-2-yn-1-yl)-2-(3-phenylprop-2-yn-1-yl)malonate (1p)

[0064] 1.2 Preparation of alkynyl boron compounds

[0065] Procedure A: 1,8-diaminonaphthalene (2 eq.), Cs2CO3 (1 eq.) and DMF (0.5 M) were added to ar. The mixture was stirred at room temperature for 30 minutes. Then, alkyl bromide (1 eq.) was added at room temperature. The reaction was stirred at 60°C for 1 hour. After the reaction was complete, the mixture was filtered through a silica gel pad and washed with EtOAc. The filtrate was concentrated under reduced pressure at 60°C. The residue was purified by silica gel column chromatography to produce an asymmetrically substituted 1,8-diaminonaphthalene product (s-1a-n, see Fig. 9 ). N 1 -Benzylnaphthalene-1,8-diamine (s-1a) s-1a was prepared from 1,8-diaminonaphthalene (9.492 g, 60 mmol) and benzyl bromide (3.6 mL, 30 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave s-1a (5.231 g, 70% yield) as a pink oil. N 1 -(4-Methylbenzyl)naphthalene-1,8-diamine (s-1b) s-1b was prepared from 1,8-diaminonaphthalene (1.898 g, 12 mmol) and 4-methylbenzyl bromide (1.111 g, 6 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave s-1b (1.120 g, 71% yield) as a pink oil. N 1 -(4-(Trifluoromethoxy)benzyl)naphthalene-1,8-diamine (s-1c) s-1c was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 4-(trifluoromethoxy)benzyl bromide (0.8 mL, 5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-7 / 1) gave s-1c (1.219 g, 74% yield) as a pink oil. N 1 -(4-Fluorobenzyl)naphthalene-1,8-diamine (s-1d) s-1d was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 4-fluorobenzyl bromide (0.62 mL, 5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave s-1d (0.976 g, 73% yield) as a pink oil. N 1 -(4-Chlorobenzyl)naphthalene-1,8-diamine (s-1e) s-1e was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 4-chlorobenzyl bromide (1.028 g, 5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave s-1e (0.960 g, 68% yield) as a pink oil. N 1 -(4-Bromobenzyl)naphthalene-1,8-diamine(s-1f) s-1f was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 4-bromobenzyl bromide (1.25 g, 5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave s-1f (1.217 g, 74% yield) as a pink oil. N 1 -(4-iodobenzyl)naphthalene-1,8-diamine (S-1g) S-1g was prepared from 1,8-diaminonaphthalene (1.898 g, 12 mmol) and 4-iodobenzyl bromide (1.782 g, 6 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave S-1g (1.866 g, 83% yield) as a pink oil. Methyl 4-(((8-aminonaphthalen-1-yl)amino)methyl)benzoate (S-1H) S-1h was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and methyl 4-(bromomethyl)benzoate (1.146 g, 5 mmol) according to the above procedure A. S-1h was purified by silica gel column chromatography (n-hexane / EA=10 / 1-4 / 1) to obtain s-1h (0.541 g, 35% yield) as an orange oil. N 1 -(3-Methylbenzyl)naphthalene-1,8-diamine (s-1i) s-1i was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 3-methylbenzyl bromide (0.68 mL, 5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave s-1i (0.846 g, 64% yield) as a pink oil. N 1 -(2-Methylbenzyl)naphthalene-1,8-diamine (s-1j) s-1j was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 2-methylbenzyl bromide (0.67 mL, 5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-5 / 1) gave s-1j (1.021 g, 78% yield) as a pink oil. N 1 -(Naphthalene-1-ylmethyl)naphthalene-1,8-diamine (s-1k) S-1k was prepared from 1,8-diaminonaphthalene (3.164 g, 20 mmol) and 1-(bromomethyl)naphthalene (2.211 g, 10 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=15 / 1-5 / 1) gave S-1k (2.028 g, 68% yield) as a pink solid. N 1 -(Naphthalene-2-ylmethyl)naphthalene-1,8-diamine (S-1L) S-11 was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 2-(bromomethyl)naphthalene (1.106 g, 5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=15 / 1-5 / 1) gave S-11 (0.988 g, 66% yield) as a red solid. N 1 -(3-Methylbut-2-en-1-yl)naphthalene-1,8-diamine (S-1m) S-1m was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 3,3-dimethylallyl bromide (0.58 mL, 5 mmol) according to the above procedure A. S-1m was purified by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) to obtain S-1m (0.678 g, 60% yield) as a pink oil. N 1 -(3-(Trimethylsilyl)prop-2-yn-1-yl)naphthalene-1,8-diamine (s-1n) S-1n was prepared from 1,8-diaminonaphthalene (1.582 g, 10 mmol) and 3-bromo-1-(trimethylsilyl)-1-propyne (0.82 mL, 5 mmol) according to the above procedure A. S-1n was purified by silica gel column chromatography (n-hexane / EA=20 / 1-7 / 1) to obtain S-1n (0.722 g, 54% yield) as a red solid.

[0066] Procedure B: 1,8-diaminonaphthalene (2 equivalents), Cs2CO3 (1 equivalent) and DMF (0.5M) are added to a round-bottom flask. The mixture is stirred at room temperature for 30 minutes. Then, alkyl iodide (1 equivalent) is added at room temperature. The reaction is stirred at 60°C for 1 hour. After the reaction is complete, the mixture is filtered through a silica gel pad and washed with EtOAc. The filtrate is concentrated under reduced pressure at 60°C. The residue is purified by silica gel column chromatography to produce an asymmetrically substituted 1,8-diaminonaphthalene product (s-1o-p). N 1 -Ethylnaphthalene-1,8-diamine (S-1o) S-1o was prepared from 1,8-diaminonaphthalene (3.164 g, 20 mmol) and iodoethane (0.8 mL, 10 mmol) according to the above procedure B. S-1o was purified by silica gel column chromatography (n-hexane / EA=30 / 1-10 / 1) to obtain S-1o (0.834 g, 45% yield) as a pink oil. N 1 -Butylnaphthalene-1,8-diamine (s-1p) s-1p was prepared from 1,8-diaminonaphthalene (3.164 g, 20 mmol) and 1-iodobutane (1.14 mL, 10 mmol) according to the above procedure B. Purification by silica gel column chromatography (n-hexane / EA=30 / 1-10 / 1) gave s-1p (0.810 g, 38% yield) as a pink oil. Procedure C: 1,8-diaminonaphthalene (1.582 g, 10 mmol), DIPEA (1.74 mL, 10 mmol), DCM (25 mL) and MeOH (5 mL) were added to a 100 mL round-bottom flask. Then, 4-(bromomethyl)phenylboronic acid pinacol ester (1.485 g, 5 mmol) was slowly added at room temperature. The reaction was stirred at room temperature for 18 hours. After the reaction was complete, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with H2O. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) to produce an asymmetrically substituted 1,8-diaminonaphthalene product s-1q. N 1 -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)naphthalene-1,8-diamine (S-1q) Following procedure C above, s-1p (0.696 g, 37% yield) was obtained as a red solid.

[0067] 1.3 Preparation of asymmetrically substituted o-aminobenzamide (aam)

[0068] Procedure: Isatoic anhydride (5 mmol), amine (5 mmol) and designated solvent (10 mL) were added to a 50 mL round bottom flask. The mixture was stirred at the designated temperature for the designated time. After the reaction was completed, the reaction mixture was quenched with H2O (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine (2×10 mL) and dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure and the residue was further purified by silica gel column chromatography to give the asymmetrically substituted o-aminobenzamide product s-2c-j. See Fig.10 .

[0069] 1.4 Preparation of alkynyl Bdan compounds

[0070] Method A: From common terminal alkynes

[0071] Procedure A: Under nitrogen atmosphere, terminal alkyne (5 mmol, 1 eq.) and dry THF (10 mL, 0.5 M) were added to a flame-dried 100 mL Schlenk flask via syringe. The mixture was cooled to -78 °C and added dropwise nBμLi (2.2mL, 2.5M in hexane, 1.1 equivalents). Afterwards, the reaction was stirred at -78 ° C for 1 hour (step 1, lithiation). Then, triisopropyl borate (1.27mL, 5.5mmol, 1.1 equivalents) was slowly added to the mixture by syringe, and the reaction was stirred at -78 ° C for 2 hours. A white slurry was formed during this stage, indicating that the tetrasubstituted boron complex was successfully formed (step 2, borylation). Next, a solution of HCl in diethyl ether (3mL, 2M, 1.2 equivalents) was slowly added to the mixture by syringe at -78 ° C, and the reaction was warmed to room temperature under stirring for 30 minutes. During this stage, the white slurry disappeared and a clear solution was formed, indicating that the neutral trisubstituted boric acid alkynyl ester was successfully formed (step 3, acidification). Afterwards, the solution was transferred to a 100mL round-bottom flask (rinsed with diethyl ether) and concentrated under reduced pressure. The residue was dissolved in 10 mL of toluene and a solution of asymmetrically substituted 1,8-diaminonaphthalene (5.5 mmol, 1.1 equiv.) in 10 mL of toluene was added. The reaction was stirred in an open flask at 110 °C for 1 hour, after which TLC of the crude mixture showed complete conversion (step 4, amination). The reaction mixture was quenched with H2O (10 mL) and EtOAc (10 mL). The layers were separated, and the organic phase was washed twice with H2O to remove the inorganic salt LiCl. The combined aqueous phases were extracted once with EA. The combined organic phases were further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a crude product, which was purified by silica gel column chromatography or washed with n-hexane to produce a pure alkynyl Bdan product. The obtained alkynyl Bdan can be stored in air at room temperature for several months without significant degradation. See Fig.11A . 1-Benzyl-2-(hept-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2a) 2a was prepared from 1-heptyne (0.68 mL, 5.2 mmol) and s-1a (1.425 g, 5.74 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=30 / 1) gave 2a (1.653 g, 90% yield) as a purple solid. 1-Benzyl-2-(hex-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2b) 2b was prepared from 1-hexyne (0.57 mL, 5 mmol) and s-1a (5.5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=30 / 1) gave 2b as a purple solid. 1-Benzyl-2-(oct-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2c) 2c was prepared from 1-octyne (1.08 mL, 6 mmol) and s-1a (6.6 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=30 / 1) gave 2c as a purple solid. 1-Benzyl-2-(4-methylpent-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2d) 2d was prepared from 4-methyl-1-pentyne (0.48 mL, 4.1 mmol) and s-1a (1.117 g, 4.5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=30 / 1) gave 2d (1.053 g, 76% yield) as a purple solid. 1-Benzyl-2-(4-phenylbut-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2e) 2e was prepared from 4-phenyl-1-butyne (0.65 mL, 4.6 mmol) and s-1a (1.266 g, 5.1 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=30 / 1) gave 2e (1.633 g, 92% yield) as a purple solid. 1-Benzyl-2-(5-chloropent-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2f) 2f was prepared from 5-chloro-1-pentyne (0.64 mL, 6 mmol) and s-1a (1.639 g, 6.6 mmol) following the above procedure A. The crude product was purified by washing with n-hexane to obtain 2f (1.904 g, 88% yield) as a pink solid. 1-Benzyl-2-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2g) 2g was prepared from 4-(tert-butyldimethylsilyloxy)-1-butyne (0.83 mL, 4 mmol) and s-1a (1.093 g, 4.4 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=30 / 1) gave 2g (1.527 g, 87% yield) as a pink oil. 4-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)but-3-yn-1-yl 4-methylbenzenesulfonate (2h) 2h was prepared from 4-methylbenzenesulfonic acid but-3-yn-1-yl ester (1.750 g, 7.8 mmol) and s-1a (2.135 g, 8.6 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=3 / 1) gave 2h (3.019 g, 81% yield) as a pink solid. 4-Methylbenzenesulfonic acid 5-(1-benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)pent-4-yn-1-yl ester (2i) 2i was prepared from pent-4-yn-1-yl 4-methylbenzenesulfonate (2.264 g, 9.5 mmol) and s-1a (2.607 g, 10.5 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=3 / 1) gave 2i (3.701 g, 79% yield) as a pink solid. 6-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)hex-5-yn-1-yl 4-methylbenzenesulfonate (2j) 2j was prepared from 4-methylbenzenesulfonic acid hex-5-yn-1-yl ester (1.153 g, 4.6 mmol) and s-1a (1.242 g, 5.0 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=3 / 1) gave 2j (1.658 g, 71% yield) as a pink solid. 1-Benzyl-2-(3-methoxyprop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2k) 2k was prepared from methyl propargyl ether (0.32 mL, 3.8 mmol) and s-1a (1.018 g, 4.1 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 2k (1.051 g, 86% yield) as a pink solid. 1-Benzyl-2-(3-(trimethylsilyl)prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2l) 21 was prepared from propargyltrimethylsilane (0.65 mL, 4 mmol) and s-1a (1.093 g, 4.4 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=50 / 1-20 / 1) gave 21 (1.145 g, 78% yield) as a black solid. 1-Benzyl-2-(3-methylbut-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2m) 2m was prepared from 3-methyl-1-butyne (0.54 mL, 5.3 mmol) and s-1a (1.440 g, 5.8 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=40 / 1-20 / 1) gave 2m (1.686 g, 98% yield) as a pink solid. 1-Benzyl-2-(cyclopropylethynyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2n) 2n was prepared from cyclopropylacetylene (0.36 mL, 4.2 mmol) and s-1a (1.142 g, 4.6 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=40 / 1) gave 2n (1.086 g, 80% yield) as a purple solid. 1-Benzyl-2-(cyclohexylethynyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl(2o) 2o was prepared from cyclohexylacetylene (0.78 mL, 6 mmol) and s-1a (1.638 g, 6.6 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=40 / 1-20 / 1) gave 2o (1.435 g, 66% yield) as a pink solid. (E)-1-Benzyl-2-(4-phenylbut-3-en-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2p) 2p was prepared from (E)-but-1-en-3-yn-1-ylbenzene (1.256 g, 9.8 mmol) and s-1a (2.682 g, 10.8 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA / DCM=20 / 1 / 1) gave 2p (2.625 g, 70% yield) as an orange solid. 1-Benzyl-2-(cyclohex-1-en-1-ylethynyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2q) 2q was prepared from 1-ethynylcyclohexene (0.58 mL, 4.9 mmol) and s-1a (1.341 g, 5.4 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=40 / 1-20 / 1) gave 2q (1.596 g, 90% yield) as a pink solid. 1-Benzyl-2-(phenylethynyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2r) 2r was prepared from phenylacetylene (0.44 mL, 4 mmol) and s-1a (1.093 g, 4.4 mmol) according to the above procedure A. Purification by silica gel column chromatography (n-hexane / EA=15 / 1-12 / 1) gave 2r (1.158 g, 81% yield) as a pink solid.

[0072] Method B: From terminal alkynes with sensitive functional groups

[0073] Procedure B: Under a nitrogen atmosphere, terminal alkynes (4.5mmol, 1 equivalent) and dry THF (9mL, 0.5M) were added to a flame-dried 100mL Schlenk flask by syringe. The mixture was cooled to -78°C, and LDA (2.5mL, 2M in THF / hexane, 1.1 equivalents) was added dropwise. Afterwards, the reaction was stirred at -78°C for 1 hour (step 1, lithiation). Then, triisopropyl borate (1.16mL, 5mmol, 1.1 equivalents) was slowly added to the mixture by syringe, and the reaction was stirred at -78°C for 2 hours. A yellow slurry was formed during this stage, indicating that a tetrasubstituted boron complex was successfully formed (step 2, borylation). Next, a solution of HCl in diethyl ether (6.75mL, 2M, 3 equivalents) was slowly added to the mixture by syringe at -78°C, and the reaction was warmed to room temperature under stirring for 30 minutes. In this procedure, due to the production of insoluble ammonium salts, the reaction mixture was stirred for 30 minutes. i Pr2NH·HCl (step 3, acidification), still presents a yellow slurry. Afterwards, the solution is filtered through a celite pad to remove a large amount of ammonium salts i Pr2NH·HCl, and the filtrate was concentrated under reduced pressure. The residue was suspended in diethyl ether, and the suspension was further filtered through a celite pad to remove the remaining ammonium salts. i Pr2NH·HCl and inorganic salt LiCl. The filtrate was concentrated under reduced pressure and transferred to a 100 mL round-bottom flask. The residue was dissolved in 10 mL of toluene and a solution of asymmetrically substituted 1,8-diaminonaphthalene (5 mmol, 1.1 equiv.) in 10 mL of toluene was added. The reaction was stirred in an open flask at 110 °C for 1 hour, after which TLC of the crude mixture showed complete conversion (step 4, amination). The reaction mixture was quenched with H2O (10 mL) and EtOAc (10 mL). The layers were separated and the organic phase was washed twice with H2O. The combined aqueous phases were extracted once with EA. The combined organic phases were further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a crude product, which was purified by silica gel column chromatography to produce a pure alkynyl Bdan product. The obtained alkynyl Bdan can be stored in air at room temperature for several months without significant degradation. See Fig. 11B . 4-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)but-3-yn-1-yl benzoate (2s) 2s was prepared from 3-yn-1-yl benzoate (0.784 g, 4.5 mmol) and s-1a (1.242 g, 5 mmol) according to the above procedure B. Purification by silica gel column chromatography (n-hexane / EA=15 / 1-7 / 1) gave 2s (0.985 g, 51% yield) as a pink solid. 4-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)but-3-yn-1-yl 4-(N,N-dipropylaminosulfonyl)benzoate (2t) 2t is derived from probenecid. First, according to the literature 14 Preparation of alkyne-2t. Then, 2t was prepared from alkyne-2t (1.123 g, 3.3 mmol) and s-1a (0.901 g, 3.6 mmol) according to the above procedure B. Purification by silica gel column chromatography (n-hexane / EA=5 / 1-2 / 1) gave 2t (0.752 g, 38% yield) as a white solid. 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid 5-(1-benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)pent-4-yn-1-yl ester (2u) 2u is derived from gemfibrozil. First, alkyne-2u is prepared. Then, 2u was prepared from alkyne-2u (0.814 g, 2.57 mmol) and s-1a (0.703 g, 2.83 mmol) according to the above procedure B. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 2u (0.420 g, 29% yield) as a pink oil.

[0074] Method C: From Grignard reagent

[0075] Procedure C: Under nitrogen atmosphere, trimethyl borate (0.63mL, 5.5mmol, 1.1 equivalents) and dry THF (10mL, 0.5M) were added to a flame-dried 50mL Schlenk flask by syringe. The mixture was cooled to -78°C, and 1-propynyl magnesium bromide (10mL, 0.5M in THF, 1 equivalent) was added dropwise. Afterwards, the reaction was warmed to room temperature under stirring for 2 hours. During this stage, a white slurry was formed, indicating that the tetrasubstituted boron complex was successfully formed (step 1, borylation). Next, the mixture was cooled to -78°C again, and a solution of HCl in diethyl ether (3.5mL, 2M, 1.4 equivalents) was slowly added by syringe. The reaction was warmed to room temperature under stirring for 1 hour. During this stage, the white slurry disappeared and a clear solution was formed, indicating that the neutral trisubstituted boric acid alkynyl ester was successfully formed (step 2, acidification). After that, the stopper was removed and a solution of asymmetrically substituted 1,8-diaminonaphthalene (5.5 mmol, 1.1 eq) in 5 mL of THF was added. The reaction was stirred in an open Schlenk flask at 80 °C for 3 hours, after which TLC of the crude mixture showed complete conversion (step 3, amination). The reaction mixture was quenched with H2O (10 mL) and EtOAc (10 mL). The layers were separated, and the organic phase was washed twice with H2O to remove inorganic salts MgCl2, MgBr2. The combined aqueous phases were extracted once with EA. The combined organic phases were further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a crude product, which was purified by silica gel column chromatography or washed with n-hexane to produce a pure alkynyl Bdan product. The obtained alkynyl Bdan can be stored in air at room temperature for several months without significant degradation. See Fig. 11C . 1-Benzyl-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2v) 2v was prepared from 1-propynylmagnesium bromide (20 mL, 10 mmol) and s-1a (2.731 g, 11 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2v (2.232 g, 75% yield) as a pink solid. 1-(4-Methylbenzyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2aa) 2aa was prepared from 1-propynylmagnesium bromide (7.4 mL, 3.7 mmol) and s-1b (1.076 g, 4.1 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2aa (0.700 g, 61% yield) as a pink solid. 2-(Prop-1-yn-1-yl)-1-(4-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ab) 2ab was prepared from 1-propynylmagnesium bromide (6.6 mL, 3.3 mmol) and s-1c (1.196 g, 3.6 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ab (0.887 g, 71% yield) as a pink solid. 1-(4-Fluorobenzyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ac) 2ac was prepared from 1-propynylmagnesium bromide (6.6 mL, 3.3 mmol) and s-1d (0.959 g, 3.6 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ac (0.826 g, 80% yield) as a pink solid. 1-(4-Chlorobenzyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ad) 2ad was prepared from 1-propynylmagnesium bromide (6 mL, 3 mmol) and s-1e (0.933 g, 3.3 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ad (0.571 g, 58% yield) as a pink solid. 1-(4-Bromobenzyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ae) 2ae was prepared from 1-propynylmagnesium bromide (6.6 mL, 3.3 mmol) and s-1f (1.178 g, 3.6 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ae (0.836 g, 68% yield) as a pink solid. 1-(4-iodobenzyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2af) 2af was prepared from 1-propynylmagnesium bromide (8.9 mL, 4.45 mmol) and s-1g (1.834 g, 4.9 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2af (1.343 g, 72% yield) as a pink solid. 2-(Propan-1-yn-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ag) 2ag was prepared from 1-propynylmagnesium bromide (4.7 mL, 2.35 mmol) and s-1q (0.973 g, 2.6 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ag (0.712 g, 71% yield) as a pink solid. Methyl 4-((2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborin-1-yl)methyl)benzoate (2ah) 2ah was prepared from 1-propynylmagnesium bromide (3.2 mL, 1.6 mmol) and s-1h (0.539 g, 1.76 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ah (0.445 g, 78% yield) as an orange solid. 1-(3-Methylbenzyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ai) 2ai was prepared from 1-propynylmagnesium bromide (5.8 mL, 2.9 mmol) and s-1i (0.840 g, 3.2 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ai (0.638 g, 71% yield) as a purple solid. 1-(2-Methylbenzyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2aj) 2aj was prepared from 1-propynylmagnesium bromide (7.1 mL, 3.55 mmol) and s-1j (1.023 g, 3.9 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2aj (0.789 g, 72% yield) as a pink solid. 1-(Naphthalen-1-ylmethyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ak) 2ak was prepared from 1-propynylmagnesium bromide (6 mL, 3 mmol) and s-1k (0.985 g, 3.3 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2ak (0.933 g, 90% yield) as a pink solid. 1-(Naphthalen-2-ylmethyl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2al) 2al was prepared from 1-propynylmagnesium bromide (6 mL, 3 mmol) and s-11 (0.985 g, 3.3 mmol) following the above procedure C. Purification by washing with n-hexane afforded 2al as a pink solid (0.804 g, 77% yield). 1-Ethyl-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2am) 2am was prepared from 1-propynylmagnesium bromide (6 mL, 3 mmol) and s-1o (0.615 g, 3.3 mmol) according to the above procedure C. Purification by silica gel column chromatography (n-hexane / EA=40 / 1) gave 2am (0.617 g, 88% yield) as a pink solid. 1-Butyl-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2an) 2an was prepared from 1-propynylmagnesium bromide (4.2 mL, 2.1 mmol) and s-1p (0.493 g, 2.3 mmol) according to the above procedure C. Purification by silica gel column chromatography (n-hexane / EA=40 / 1) gave 2an (0.491 g, 89% yield) as a pink solid. 1-(3-Methylbut-2-en-1-yl)-2-(prop-1-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ao) 2ao was prepared from 1-propynylmagnesium bromide (5.4 mL, 2.7 mmol) and s-1m (0.679 g, 3 mmol) according to the above procedure C. Purification by silica gel column chromatography (n-hexane / EA=40 / 1) gave 2ao (0.539 g, 73% yield) as a pink solid. 2-(Prop-1-yn-1-yl)-1-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (2ap) 2ap was prepared from 1-propynylmagnesium bromide (4.6 mL, 2.3 mmol) and s-1m (0.676 g, 2.5 mmol) according to the above procedure C. Purification by silica gel column chromatography (n-hexane / EA=40 / 1) gave 2ap (0.330 g, 45% yield) as a pink solid.

[0076] 1.5 Preparation of alkynyl Baam compounds

[0077] Method A: From common terminal alkynes

[0078] Procedure A: Under nitrogen atmosphere, terminal alkyne (5 mmol, 1 eq.) and dry THF (10 mL, 0.5 M) were added to a flame-dried 100 mL Schlenk flask via syringe. The mixture was cooled to -78 °C and added dropwise nBμLi (2.2mL, 2.5M in hexane, 1.1 equivalents). Afterwards, the reaction was stirred at -78 ° C for 1 hour (step 1, lithiation). Then, triisopropyl borate (1.27mL, 5.5mmol, 1.1 equivalents) was slowly added to the mixture by syringe, and the reaction was stirred at -78 ° C for 2 hours. A white slurry was formed during this stage, indicating that the tetrasubstituted boron complex was successfully formed (step 2, borylation). Next, a solution of HCl in diethyl ether (3mL, 2M, 1.2 equivalents) was slowly added to the mixture by syringe at -78 ° C, and the reaction was warmed to room temperature under stirring for 30 minutes. During this stage, the white slurry disappeared and a clear solution was formed, indicating that the neutral trisubstituted boric acid alkynyl ester was successfully formed (step 3, acidification). Afterwards, the solution was transferred to a 100mL round-bottom flask (rinsed with diethyl ether) and concentrated under reduced pressure. The residue was dissolved in 20 mL of toluene and asymmetrically substituted o-aminobenzamide (5 mmol, 1 eq.) was added. The reaction was stirred in an open flask at 110 °C for 3 hours, after which TLC of the crude mixture showed complete conversion (step 4, amination). The reaction mixture was quenched with H2O (10 mL) and EtOAc (10 mL). The layers were separated, and the organic phase was washed twice with H2O to remove the inorganic salt LiCl. The combined aqueous phases were extracted once with EA. The combined organic phases were further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a crude product, which was purified by recrystallization or flash column chromatography to produce a pure alkynyl Baam product. The obtained alkynyl Baam can be stored in air at room temperature for several months without significant degradation. See Fig. 12A . 2-(Hept-1-yn-1-yl)-3-methyl-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2ba) 2ba was prepared from 1-heptyne (0.66 mL, 5 mmol) and s-2a (0.751 g, 5 mmol) following the above procedure A. Purification by recrystallization from toluene (4 mL) afforded 2ba (1.167 g, 92% yield) as a white solid. 2-(5-Chloropent-1-yn-1-yl)-3-methyl-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bb) 2bb was prepared from 5-chloro-1-pentyne (0.64 mL, 6 mmol) and s-2a (0.9 g, 6 mmol) following the above procedure A. Purification by recrystallization from toluene (4 mL) afforded 2bb (1.431 g, 92% yield) as a white solid. 3-Butyl-2-(5-chloropent-1-yn-1-yl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bc) 2bc was prepared from 5-chloro-1-pentyne (0.45 mL, 4.2 mmol) and s-2c (0.808 g, 4.2 mmol) following the above procedure A. Purification by recrystallization from toluene (2 mL) afforded 2bc (1.103 g, 87% yield) as a white solid. 2-(5-Chloropent-1-yn-1-yl)-3-cyclopropyl-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bd) 2bd was prepared from 5-chloro-1-pentyne (0.40 mL, 3.8 mmol) and s-2d (0.670 g, 3.8 mmol) following the above procedure A. Purification by recrystallization from toluene (4 mL) afforded 2bd (0.951 g, 87% yield) as a white solid. Rf=0.38(silica gel, n-hexane / EA=3 / 1) 2-(Hex-1-yn-1-yl)-3-phenyl-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2be) 2be was prepared from 1-hexyne (0.46 mL, 4 mmol) and s-2e (0.849 g, 4 mmol) following the above procedure A. Purification by recrystallization from toluene (10 mL) afforded 2be (1.060 g, 88% yield) as a light yellow solid. 2-(4-phenylbut-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bf) 2bf was prepared from 4-phenyl-1-butyne (0.34 mL, 2.4 mmol) and s-2f (0.524 g, 2.4 mmol) following the above procedure A. Purification by recrystallization from toluene (4 mL) afforded 2bf (0.686 g, 80% yield) as a white solid. 3-Benzyl-2-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bg) 2bg was prepared from 4-(tert-butyldimethylsilyloxy)-1-butyne (0.89 mL, 4.3 mmol) and s-2g (0.973 g, 4.3 mmol) according to the above procedure A. Purification by flash column chromatography (n-hexane / EA=5 / 1) gave 2bg (1.116 g, 62% yield) as a white solid. 3-Cyclohexyl-2-(4-phenylbut-1-yn-1-yl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bh) 2bh was prepared from 4-phenyl-1-butyne (0.46 mL, 3.3 mmol) and s-2h (0.786 g, 3.6 mmol) according to the above procedure A. Purification by flash column chromatography (n-hexane / EA=5 / 1) gave 2bh (0.960 g, 82% yield) as a white solid. (R)-2-(5-chloropent-1-yn-1-yl)-3-(1-phenylethyl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bi) 2bi was prepared from 5-chloro-1-pentyne (0.42 mL, 4 mmol) and s-2i (0.961 g, 4 mmol) according to the above procedure A. Purification by flash column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 2bi (0.986 g, 70% yield) as a white foam. (S)-2-(5-chloropent-1-yn-1-yl)-3-(1-phenylethyl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bj) 2bj was prepared from 5-chloro-1-pentyne (0.47 mL, 4.4 mmol) and s-2j (1.057 g, 4.4 mmol) according to the above procedure A. Purification by flash column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 2bj (1.033 g, 67% yield) as a white foam. 2-(Hept-1-yn-1-yl)-1-methyl-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bk) 2bk was prepared from 1-heptyne (0.66 mL, 5 mmol) and s-2b (0.751 g, 5 mmol) following the above procedure A. Purification by recrystallization from toluene afforded 2bk as a white solid. 1-Benzyl-2-(4-phenylbut-1-yn-1-yl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bl) 2bl was prepared from 4-phenyl-1-butyne (0.38 mL, 2.7 mmol) and s-2k (0.611 g, 2.7 mmol) following the above procedure A. Purification by recrystallization from toluene (4 mL) afforded 2bl (0.892 g, 91% yield) as a white solid.

[0079] Method B: From Grignard reagent

[0080] Procedure B: Under nitrogen atmosphere, trimethyl borate (0.5mL, 4.4mmol, 1.1 equivalents) and dry THF (8mL, 0.5M) were added to a flame-dried 50mL Schlenk flask by syringe. The mixture was cooled to -78°C, and 1-propynyl magnesium bromide (8mL, 0.5M in THF, 1 equivalent) was added dropwise. Afterwards, the reaction was warmed to room temperature under stirring for 2 hours. During this stage, a white slurry was formed, indicating that the tetrasubstituted boron complex was successfully formed (step 1, borylation). Next, the mixture was cooled to -78°C again, and a solution of HCl in diethyl ether (2.8mL, 2M, 1.4 equivalents) was slowly added by syringe. The reaction was warmed to room temperature under stirring for 1 hour. During this stage, the white slurry disappeared and a clear solution was formed, indicating that the neutral trisubstituted boric acid alkynyl ester was successfully formed (step 2, acidification). Afterwards, the prepared boric acid alkynyl ester solution was added dropwise at 110°C to another 100ml round-bottom flask containing s-2a (0.601g, 4mmol, 1 equivalent) and toluene (16mL). After the addition was complete, the Schlenk flask was washed with 4mL toluene and the washings were added to the mixture. The reaction was stirred in an open flask at 110°C for 3 hours (step 3, amination). The reaction mixture was quenched with H2O (10mL) and EtOAc (10mL). The layers were separated, and the organic phase was washed twice with H2O to remove the inorganic salts MgCl2, MgBr2. The combined aqueous phase was extracted once with EA. The combined organic phases were further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a crude product, which was purified by flash column chromatography (n-hexane / EA=3 / 1) to produce a pure alkynyl Baam product 2bm (0.128g, 16% yield). 2bm can be stored in air at room temperature for several months without significant degradation. Fig. 12B . 3-Methyl-2-(prop-1-yn-1-yl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (2bm) 2bm was prepared from 1-propynylmagnesium bromide (8 mL, 4 mmol) and s-2a (0.601 g, 4 mmol) according to the above procedure B. Purification by flash column chromatography (n-hexane / EA=3 / 1) gave 2bm (0.128 g, 16% yield) as a white solid.

[0081] 1.6 Preparation of chiral MOP ligands

[0082] refer to Fig.13A Chiral MOP ligands L1-L5 are known chiral ligands. L6 was similarly prepared with a modified procedure (see Fig. 13B ), as described below.

[0083] In a 100mL round-bottom flask, (R)-BINOL (1.432g, 5mmol) was dissolved in DCM (20mL). Pyridine (1.2mL, 15mmol, 3 equivalents) was added to the solution by a syringe. The mixture was cooled to 0 ° C and trifluoromethanesulfonic anhydride (1.85mL, 11mmol, 2.2 equivalents) was added dropwise. The reaction was warmed to room temperature and stirred for 2 hours. After the reaction was completed, water (10mL) was slowly added to quench the reaction. Each layer was separated, and the aqueous phase was extracted three times with DCM. The combined organic phase was further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure, to produce a crude product, which was purified by silica gel column chromatography (n-hexane / EA=20 / 1) to produce s-3a (2.627g, 95% yield) as a colorless oil.

[0084] Pd(OAc)2(52.6mg, 0.235mmol, 5mol%), dppb(100.2mg, 0.235mmol, 5mol%), bis(p-tolyl)phosphine oxide(2.187g, 9.5mmol, 2 equivalents) were loaded into a 100mL Schlenk flask equipped with a magnetic stirring bar. The flask was sealed with a rubber stopper, evacuated and filled with nitrogen three times. Then, DMSO(20mL) and DIPEA(3.1mL, 18.8mmol, 4 equivalents) containing s-3a(4.7mmol) were added by syringe. The reaction was stirred overnight at 100°C. After the reaction was complete, water(20mL) and EA(20mL) were added to quench the reaction. Each layer was separated, and the organic phase was washed with water three times. The combined aqueous phase was extracted once with EA. The combined organic phase was further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (n-hexane / EA=1 / 1-1 / 2) to give s-3b (2.378 g, 80% yield) as a yellow foam.

[0085] In a 100mL round-bottom flask, s-3b (3.7mmol) was dissolved in dioxane (14mL) and MeOH (7mL). The mixture was cooled to 0°C and 3M NaOH aqueous solution (14.8mL, 44.4mmol, 12 equivalents) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. After the reaction was complete, water (10mL) and EA (10mL) were added to quench the reaction. Each layer was separated, and the aqueous phase was extracted three times with EA. The combined organic phase was further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a crude product, which was purified by silica gel column chromatography (n-hexane / EA=1 / 1) to produce s-3c (1.758g, 92% yield) as a yellow solid.

[0086] S-3c (3.4mmol) is loaded into a 100mL Schlenk flask equipped with a magnetic stirring bar. The flask is sealed with a rubber stopper, evacuated and filled three times with nitrogen. Then, dry toluene (34mL) and triethylamine (9.45mL, 68mmol, 20 equivalents) are added by syringe. The mixture is cooled to 0 ° C and trichlorosilane (1.7mL, 17mmol, 5 equivalents) is added dropwise by syringe. After the addition is complete, the reaction is heated to 110 ° C and stirred for 3 hours. After the reaction terminates, the reaction is cooled to room temperature and diluted with EA. Saturated NaHCO3 aqueous solution is slowly added to quench the reaction. The resulting suspension is filtered, and the filter cake is washed with EA. The filtrate is separated, and the aqueous phase is extracted three times with EA. The combined organic phase was further washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) to give L6 (1.165 g, 71% yield) as a white solid.

[0087] ent-L6 (S configuration) was prepared from (S)-BINOL (CAS: 18531-99-2) by the same procedure. (R)-[1,1'-binaphthyl]-2,2'-diylbis(trifluoromethanesulfonate) (s-3a) (R)-2'-(di-p-tolylphosphoryl)-[1,1'-binaphthyl]-2-yl trifluoromethanesulfonate (s-3b) (R)-(2'-Hydroxy-[1,1'-binaphthyl]-2-yl)di-p-tolylphosphine oxide (s-3c) (R)-2'-(di-p-tolylphosphatyl)-[1,1'-binaphthyl]-2-ol (L6)

[0088] 2. Rh-catalyzed atrop-selective [2+2+2] cycloaddition for the synthesis of axially chiral arylboron compounds (substrate scope study)

[0089] 2.1 General procedures for chiral synthesis

[0090] Rh(cod)2OTf (4.7 mg, 5 mol%), L6 (4.8 mg, 5 mol%), diyne 1 (0.2 mmol if solid) and alkynyl boron 2 (0.3 mmol) were loaded into an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar. The tube was sealed with a rubber stopper, evacuated and filled with nitrogen three times. Dry toluene (2 mL, 0.1 M) and diyne 1 (0.2 mmol if liquid) were then added sequentially by syringe. Unless otherwise stated, the reaction was stirred at 60 ° C for 20 hours, and TLC showed that diyne 1 was completely converted. Afterwards, the mixture was filtered through a short silica gel pad and rinsed with EA. The filtrate was concentrated under reduced pressure to produce a crude product, which was purified by silica gel column chromatography to produce an axial chiral arylboron compound. The separation yield was calculated by chiral HPLC and the ee value was determined.

[0091] 2.2 General procedure for racemic synthesis

[0092] Rh(cod)2OTf(1.2mg, 5mol%), PPh3(1.3mg, 10mol%), diyne 1 (if solid, 0.05mmol) and alkynyl boron 2(0.05mmol) were loaded into an oven-dried 10mL Schlenk tube equipped with a magnetic stirring bar. The tube was sealed with a rubber stopper, evacuated and filled with nitrogen three times. Then, dry toluene (0.5mL, 0.1M) and diyne 1 (if liquid, 0.05mmol) were added successively by a syringe. The reaction was stirred at 60°C for 20 hours. Afterwards, the mixture was filtered through a short silica gel pad and rinsed with EA. The filtrate was concentrated under reduced pressure to produce a crude product, which was purified by preparative thin layer chromatography to produce a racemic compound.

[0093] 2.3 Products of a series of reactions of diynes 1 and 2a (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-pentyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (3a) Following the general procedure, 3a was prepared from 1a (47.3 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 3a (106.1 mg, 90% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-diethyl-6-pentyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (3b) Following the general procedure, 3b was prepared from 1b (52.9 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 3b (102.5 mg, 83% yield) as a white solid. (S)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-pentyl-4,7-diphenyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (3c) According to the general procedure, 3c was prepared from 1c (72.1 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). In this case, the reaction time was 66 hours. Purification by silica gel column chromatography (n-hexane / EA=15 / 1-9 / 1) gave 3c (107.8 mg, 76% yield) as a white solid. Following the general procedure, 3d was prepared from 1d (40.9 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-8 / 1) gave 3d (101.5 mg, 91% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-pentyl-1,3-dihydro-2H-indene-2,2-dicarbonitrile (3e) Following the general procedure, 3e was prepared from 1e (34.0 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 3e (75.9 mg, 73% yield) as a white solid. (R)-1-Benzyl-2-(2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-4,7-dimethyl-6-pentyl-2,3-dihydro-1H-inden-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (3f) According to the general procedure, 3f was prepared from 1f (81.8 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). First, it was purified by silica gel column chromatography (n-hexane / EA=100 / 1) to produce a crude product containing a small amount of 2a, which was purified by preparative thin layer chromatography (n-hexane / EA=30 / 1) to produce pure 3f (132.0 mg, 87% yield) as a colorless oil. (R)-1-Benzyl-2-(2,2-bis(methoxymethyl)-4,7-dimethyl-6-pentyl-2,3-dihydro-1H-inden-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (3g) Following the general procedure, 3g was prepared from 1g (41.7 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / DCM=1 / 1) afforded 3g (102.1 mg, 91% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-pentyl-2-phenyl-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester (3h) According to the general procedure, 3h was prepared from 1h (50.9 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1) gave 3h (67.1 mg, 55% yield) as a white solid containing a pair of diastereomers. 1 H-NMR analysis showed a diastereoisomer ratio of 3 / 1. (R)-5'-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,4,4',7'-tetramethyl-6'-pentyl-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-2,6-dione (3i) Following the general procedure, 3i was prepared from 1i (48.9 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-9 / 1) gave 3i (76.1 mg, 64% yield) as a white solid. (R)-5'-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4',7'-dimethyl-6'-pentyl-1',3'-dihydro-2,2'-spirobi[indene]-1,3-dione (3j) Following the general procedure, 3j was prepared from 1j (50.1 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-8 / 1) gave 3j (97.2 mg, 81% yield) as a yellow solid. (R)-1-Benzyl-2-(4',7'-dimethyl-5'-pentyl-1',3'-dihydrospiro[fluorene-9,2'-indene]-6'-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (3k) According to the general procedure, 3k was prepared from 1k (54.1 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). It was first purified by silica gel column chromatography (n-hexane / EA=100 / 1) to give a crude product containing a small amount of 2a, which was purified by preparative thin layer chromatography (n-hexane / EA=50 / 1) to give pure 3k (72.0 mg, 58% yield) as an orange solid. (R)-1-Benzyl-2-(7,10-dimethyl-9-pentylfluoranthene-8-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (3l) According to the general procedure, 31 was prepared from 11 (40.9 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). It was first purified by silica gel column chromatography (n-hexane / EA=200 / 1) to give a crude product containing a small amount of 2a, which was purified by preparative thin layer chromatography (n-hexane / EA=60 / 1) to give pure 31 (52.8 mg, 47% yield) as an orange solid. (R)-1-Benzyl-2-(4,7-dimethyl-6-pentyl-2-toluenesulfonylisoindolin-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (3m) Following the general procedure, 3m was prepared from 1m (55.1 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=12 / 1-8 / 1) gave 3m (75.1 mg, 60% yield) as a white solid. (R)-1-Benzyl-2-(2-((4-bromophenyl)sulfonyl)-4,7-dimethyl-6-pentylisoindolin-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (3n) Following the general procedure, 3n was prepared from 1n (68.0 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 3n (89.6 mg, 65% yield) as a white solid. (R)-1-Benzyl-2-(4,7-dimethyl-6-pentyl-1,3-dihydroisobenzofuran-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (3o) According to the general procedure, 3o was prepared from 1o (24.4 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / DCM=2 / 1-1 / 1) gave 3o as a white solid. When 1o was added directly to the reaction, 3o was obtained in a yield of 26% (24.6 mg). When 1o was dissolved in 2 mL of dry toluene and the solution was added dropwise to the reaction for 3 hours, 3o was obtained in a yield of 62% (58.8 mg). (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4-methyl-6-pentyl-7-phenyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (3pa) / (S)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-7-methyl-6-pentyl-4-phenyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (3pb) According to the general procedure, 3pa and 3pb were prepared from 1p (59.7 mg, 0.2 mmol) and 2a (105.7 mg, 0.3 mmol). The reaction produced a pair of positional isomers (3pa, 3pb). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) produced a mixture of 3pa and 3pb as a colorless oil with an overall yield of 97% (126.8 mg). 1 H-NMR analysis showed that the positional isomer ratio was 1.44 / 1 (3 pa / 3 pb).

[0094] 2.4 Products of the reaction of diyne 1 with a series of alkynyl Bdan2a (S)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4a) Following the general procedure, 4a was prepared from 1a (47.3 mg, 0.2 mmol) and 2v (88.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4a (106.3 mg, 99% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (ent-4a) According to the general procedure, ent-4a was prepared from 1a (47.3 mg, 0.2 mmol) and 2v (88.9 mg, 0.3 mmol) by using ent-L6 as a ligand. Ent-4a (106.2 mg, 99% yield) was obtained as a white solid by purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1). (S)-1-Benzyl-2-(4,6,7-trimethyl-2-toluenesulfonylisoindolin-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (4b) Following the general procedure, 4b was prepared from 1m (55.1 mg, 0.2 mmol) and 2v (88.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=9 / 1-5 / 1) gave 4b (83.0 mg, 73% yield) as a white solid. (S)-1-Benzyl-2-(4,6,7-trimethyl-1,3-dihydroisobenzofuran-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (4c) According to the general procedure, 4c was prepared from 1o (24.4 mg, 0.2 mmol) and 2v (88.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=30 / 1-20 / 1) gave 4c as a white solid. When 1o was added directly to the reaction, 4c was obtained in a yield of 40% (33.6 mg). When 1o was dissolved in 2 mL of dry toluene and the solution was added dropwise to the reaction for 3 hours, 4c was obtained in a yield of 60% (50.5 mg). (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-diethyl-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4d) Following the general procedure, 4d was prepared from 1a (47.3 mg, 0.2 mmol) and 2b (101.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 4d (99.6 mg, 87% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-octyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4e) Following the general procedure, 4e was prepared from 1a (47.3 mg, 0.2 mmol) and 2c (101.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 4e (109.4 mg, 87% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-isobutyl-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4f) Following the general procedure, 4f was prepared from 1a (47.3 mg, 0.2 mmol) and 2d (101.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4f (91.8 mg, 80% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenylethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4 g) Following the general procedure, 4g was prepared from 1a (47.3 mg, 0.2 mmol) and 2e (115.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-8 / 1) afforded 4g (123.6 mg, 99% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(3-chloropropyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4h) Following the general procedure, 4h was prepared from 1a (47.3 mg, 0.2 mmol) and 2f (107.6 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4h (117.0 mg, 98% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4i) Following the general procedure, 4i was prepared from 1a (47.3 mg, 0.2 mmol) and 2g (132.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4i (112.0 mg, 83% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-(2-(tosyloxy)ethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4j) Following the general procedure, 4j was prepared from 1a (47.3 mg, 0.2 mmol) and 2h (144.1 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=5 / 1-3 / 1) gave 4j (143.0 mg, 99% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-(3-(tosyloxy)propyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4k) Following the general procedure, 4k was prepared from 1a (47.3 mg, 0.2 mmol) and 2i (148.3 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=5 / 1-3 / 1) gave 4k (135.6 mg, 93% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-(4-(tosyloxy)butyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4l) Following the general procedure, 41 was prepared from 1a (47.3 mg, 0.2 mmol) and 2j (152.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=6 / 1-4 / 1) gave 41 (137.9 mg, 93% yield) as a white solid. (R)-5-(2-(Benzoyloxy)ethyl)-6-(1-benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4m) Following the general procedure, 4m was prepared from 1a (47.3 mg, 0.2 mmol) and 2s (129.1 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-6 / 1) gave 4m (132.4 mg, 99% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(methoxymethyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4n) Following the general procedure, 4n was prepared from 1a (47.3 mg, 0.2 mmol) and 2k (97.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4m (112.2 mg, 99% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-((trimethylsilyl)methyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4o) Following the general procedure, 4o was prepared from 1a (47.3 mg, 0.2 mmol) and 21 (110.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4o (105.4 mg, 87% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-isopropyl-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4p) Following the general procedure, 4p was prepared from 1a (47.3 mg, 0.2 mmol) and 2m (97.3 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4p (60.1 mg, 54% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-cyclopropyl-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4q) Following the general procedure, 4q was prepared from 1a (47.3 mg, 0.2 mmol) and 2n (96.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 4q (102.1 mg, 91% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-cyclohexyl-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4r) Following the general procedure, 4r was prepared from 1a (47.3 mg, 0.2 mmol) and 2o (109.3 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4r (48.7 mg, 41% yield) as a white solid. (R)-(E)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenylvinyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4s) Following the general procedure, 4s was prepared from 1a (47.3 mg, 0.2 mmol) and 2p (115.3 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-5 / 1) gave 4s (123.1 mg, 99% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(cyclohex-1-en-1-yl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4t) Following the general procedure, 4t was prepared from 1a (47.3 mg, 0.2 mmol) and 2q (108.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4t (51.6 mg, 43% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (4u) Following the general procedure, 4u was prepared from 1a (47.3 mg, 0.2 mmol) and 2r (107.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 4u (63.4 mg, 53% yield) as a white solid. (S)-4,5,7-Trimethyl-6-(1-(4-methylbenzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5a) Following the general procedure, 5a was prepared from 1a (47.3 mg, 0.2 mmol) and 2aa (93.1 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5a (109.3 mg, 99% yield) as a white solid. (S)-4,5,7-trimethyl-6-(1-(4-(trifluoromethoxy)benzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5b) Following the general procedure, 5b was prepared from 1a (47.3 mg, 0.2 mmol) and 2ab (114.1 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5b (123.1 mg, 99% yield) as a white solid. (S)-5-(1-(4-Fluorobenzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5c) Following the general procedure, 5c was prepared from 1a (47.3 mg, 0.2 mmol) and 2ac (94.3 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5c (109.7 mg, 99% yield) as a white solid. (S)-5-(1-(4-chlorobenzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5d) Following the general procedure, 5d was prepared from 1a (47.3 mg, 0.2 mmol) and 2ad (99.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5d (113.1 mg, 99% yield) as a white solid. (S)-5-(1-(4-bromobenzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5e) Following the general procedure, 5e was prepared from 1a (47.3 mg, 0.2 mmol) and 2ae (112.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5e (121.4 mg, 99% yield) as a white solid. (S)-5-(1-(4-iodobenzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5f) Following the general procedure, 5f was prepared from 1a (47.3 mg, 0.2 mmol) and 2af (126.6 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-9 / 1) gave 5f (101.0 mg, 77% yield) as a white solid. (S)-4,5,7-trimethyl-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-naphtho[1,8-de][1,3,2]diazaborol-2(3H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5 g) Following the general procedure, 5g was prepared from 1a (47.3 mg, 0.2 mmol) and 2ag (126.6 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-9 / 1) afforded 5g (117.2 mg, 89% yield) as a white solid. (S)-5-(1-(4-(methoxycarbonyl)benzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5h) Following the general procedure, 5h was prepared from 1a (47.3 mg, 0.2 mmol) and 2ah (106.3 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 5h (117.7 mg, 99% yield) as a white solid. (S)-4,5,7-trimethyl-6-(1-(3-methylbenzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5i) Following the general procedure, 5i was prepared from 1a (47.3 mg, 0.2 mmol) and 2ai (93.1 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5i (108.7 mg, 99% yield) as a white solid. (S)-4,5,7-trimethyl-6-(1-(2-methylbenzyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5j) Following the general procedure, 5j was prepared from 1a (47.3 mg, 0.2 mmol) and 2aj (93.1 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5j (108.9 mg, 99% yield) as a white solid. (S)-4,5,7-trimethyl-6-(1-(naphthalen-1-ylmethyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5k) Following the general procedure, 5k was prepared from 1a (47.3 mg, 0.2 mmol) and 2ak (103.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-9 / 1) gave 5k (116.1 mg, 99% yield) as a white solid. (S)-4,5,7-trimethyl-6-(1-(naphthalen-2-ylmethyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5l) Following the general procedure, 51 was prepared from 1a (47.3 mg, 0.2 mmol) and 2a1 (103.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-9 / 1) gave 51 (116.8 mg, 99% yield) as a white solid. (S)-5-(1-ethyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5m) Following the general procedure, 5m was prepared from 1a (47.3 mg, 0.2 mmol) and 2am (70.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5m (93.7 mg, 99% yield) as a white solid. (S)-5-(1-Butyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5n) Following the general procedure, 5n was prepared from 1a (47.3 mg, 0.2 mmol) and 2an (78.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5n (99.3 mg, 99% yield) as a white solid. (S)-4,5,7-Trimethyl-6-(1-(3-methylbut-2-en-1-yl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5o) Following the general procedure, 5o was prepared from 1a (47.3 mg, 0.2 mmol) and 2ao (82.3 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5o (101.7 mg, 99% yield) as a white solid. (S)-4,5,7-Trimethyl-6-(1-(3-(trimethylsilyl)prop-2-yn-1-yl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (5p) Following the general procedure, 5p was prepared from 1a (47.3 mg, 0.2 mmol) and 2ap (94.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 5p (110.3 mg, 99% yield) as a white solid.

[0095] 2.5 Products of the reaction of diyne 1 with a series of alkynyl Baam2 (R)-4,7-Dimethyl-5-(3-methyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-6-pentyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6a) Following the general procedure, 6a was prepared from 1a (47.3 mg, 0.2 mmol) and 2ba (76.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=13 / 1-5 / 1) gave 6a (60.0 mg, 61% yield) as a white solid. (S)-4,5,7-trimethyl-6-(3-methyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6b) Following the general procedure, 6b was prepared from 1a (47.3 mg, 0.2 mmol) and 2bm (59.4 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=5 / 1-4 / 1) gave 6b (77.9 mg, 90% yield) as a white solid. (R)-5-(3-chloropropyl)-4,7-dimethyl-6-(3-methyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6c) Following the general procedure, 6c was prepared from 1a (47.3 mg, 0.2 mmol) and 2bb (78.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=5 / 1-4 / 1) gave 6c (88.3 mg, 89% yield) as a white solid. (R)-5-(3-Butyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-6-(3-chloropropyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6d) Following the general procedure, 6d was prepared from 1a (47.3 mg, 0.2 mmol) and 2bc (90.8 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=8 / 1-5 / 1) gave 6d (95.0 mg, 88% yield) as a white solid. (R)-5-(3-chloropropyl)-6-(3-cyclopropyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6e) Following the general procedure, 6e was prepared from 1a (47.3 mg, 0.2 mmol) and 2bd (86.0 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=6 / 1-4 / 1) gave 6e (83.6 mg, 80% yield) as a white solid. (R)-5-Butyl-4,7-dimethyl-6-(4-oxo-3-phenyl-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6f) Following the general procedure, 6f was prepared from 1a (47.3 mg, 0.2 mmol) and 2be (90.7 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=8 / 1-4 / 1) gave 6f (53.0 mg, 49% yield) as a white solid. (R)-4,7-Dimethyl-5-(4-oxo-3-(2,2,2-trifluoroethyl)-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-6-phenethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6 g) Following the general procedure, 6g was prepared from 1a (47.3 mg, 0.2 mmol) and 2bf (106.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=8 / 1-5 / 1) afforded 6g (93.9 mg, 79% yield) as a white solid. (R)-3-Benzyl-2-(6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,2-bis(methoxymethyl)-4,7-dimethyl-2,3-dihydro-1H-inden-5-yl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (6h) Following the general procedure, 6h was prepared from 1g (41.7 mg, 0.2 mmol) and 2bg (125.5 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=30 / 1-15 / 1) gave 6h (64.1 mg, 51% yield) as a white solid. (R)-1,1'-(5-(3-cyclohexyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-4,7-dimethyl-6-phenylethyl-2,3-dihydro-1H-indene-2,2-diyl)bis(ethan-1-one)(6i) Following the general procedure, 6i was prepared from 1d (40.8 mg, 0.2 mmol) and 2bh (106.9 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=9 / 1-5 / 1) gave 6h (62.8 mg, 56% yield) as a white solid. (R)-(R)-5-(3-chloropropyl)-4,7-dimethyl-6-(4-oxo-3-(1-phenylethyl)-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6j) Following the general procedure, 6j was prepared from 1a (47.3 mg, 0.2 mmol) and 2bi (105.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=8 / 1-5 / 1) gave 6j (67.2 mg, 57% yield) as a white solid. 1 H-NMR analysis showed a diastereoisomer ratio of 13 / 1. (R)-(S)-5-(3-chloropropyl)-4,7-dimethyl-6-(4-oxo-3-(1-phenylethyl)-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6k) Following the general procedure, 6k was prepared from 1a (47.3 mg, 0.2 mmol) and 2bj (105.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-4 / 1) gave 6k (46.8 mg, 40% yield) as a white solid. 1 H-NMR analysis showed a diastereoisomer ratio of 7 / 1. (R)-4,7-Dimethyl-5-(1-methyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-6-pentyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (6l) Following the general procedure, 61 was prepared from 1a (47.3 mg, 0.2 mmol) and 2bk (76.2 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=5 / 1-4 / 1) gave 61 (63.0 mg, 64% yield) as a white solid. (R)-1-Benzyl-2-(2,2-bis(methoxymethyl)-4,7-dimethyl-6-phenylethyl-2,3-dihydro-1H-inden-5-yl)-2,3-dihydrobenzo[d][1,3,2]diazaborin-4(1H)-one (6m) Following the general procedure, 6m was prepared from 1g (41.7 mg, 0.2 mmol) and 2bl (109.3 mg, 0.3 mmol). Purification by silica gel column chromatography (DCM / EA=9 / 1) gave 6m (48.7 mg, 43% yield) as a white solid.

[0096] 2.6 Later stage modification of drugs

[0097] Rhodium-catalyzed [2+2+2] cycloadditions can also be applied to late-stage modification of drugs. In the following examples, rhodium-catalyzed [2+2+2] cycloadditions have been tested on two specific drugs (probenecid and gemfibrozil). It is expected that more drugs will be compatible with this modification scheme.

[0098] (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(2-((4-(N,N-dipropylaminosulfonyl)benzoyl)oxy)ethyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (7a)

[0099] Following the general procedure, 7a was prepared from 1a (47.3 mg, 0.2 mmol) and 2t (178.1 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=6 / 1-4 / 1) gave 7a (152.0 mg, 92% yield) as a white solid.

[0100] (R)-3-(6-(1-benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-2-toluenesulfonylisoindolin-5-yl)propyl 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoate (7b)

[0101] Following the general procedure, 7b was prepared from 1m (55.1 mg, 0.2 mmol) and 2u (171.8 mg, 0.3 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-6 / 1) gave 7b (89.3 mg, 53% yield) as a white solid.

[0102] 3. Conversion of CB atropisomers

[0103] 3.1 Basic functional group transformation

[0104] 4h (357mg, 0.6mmol) and NaSPh (158.6mg, 1.2mmol) are loaded into an oven-dried 25mL Schlenk flask equipped with a magnetic stirring bar. The flask is sealed with a rubber stopper, evacuated and filled with nitrogen three times. Then, DMF (6mL, 0.1M) is added by a syringe. The reaction is stirred at room temperature for 2 hours, and crude NMR shows that 4h is completely converted. Afterwards, brine (10mL) and EA (10mL) are added, and each layer is separated. The organic phase is washed three times with brine (3×10mL), and the combined aqueous phase is extracted once with EA (10mL). The combined organic phase is dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1), to produce 8a (324mg, 81% yield) as a white solid. (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-(3-(phenylthio)propyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (8a)

[0105] 4k (730.7 mg, 1 mmol) and NaI (300 mg, 2 mmol) were loaded into an oven-dried 25 mL Schlenk flask equipped with a magnetic stirring bar. The flask was sealed with a rubber stopper, evacuated and filled with nitrogen three times. Then, acetone (5 mL, 0.2 M) was added by syringe. The reaction was stirred at 60 ° C for 24 hours, and TLC showed that 4k was completely converted. Afterwards, the mixture was filtered through a short silica gel pad and rinsed with EA. The filtrate was concentrated under reduced pressure to produce a crude product, which was purified by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) to produce 8b (629.6 mg, 92% yield) as a white solid.

[0106] (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(3-iodopropyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (8b)

[0107] 8b (343.2 mg, 0.5 mmol), TBAI (36.9 mg, 0.1 mmol), diphenylphosphine oxide (202.2 mg, 1 mmol) and K2CO3 (138.2 mg, 1 mmol) were loaded into an oven-dried 25 mL Schlenk flask equipped with a magnetic stirring bar. The flask was sealed with a rubber stopper, evacuated and filled with nitrogen three times. Then, DMF (5 mL, 0.1 M) was added by syringe. The reaction was stirred at 70 ° C for 15 hours, and TLC showed that 8b was fully converted. Afterwards, brine (10 mL) and EA (10 mL) were added, and the layers were separated. The organic phase was washed three times with brine (3 × 10 mL), and the combined aqueous phase was extracted once with EA (10 mL). The combined organic phase was dried over Na 2 SO 4 , concentrated under reduced pressure, and purified by silica gel column chromatography (toluene / EA=1 / 1) to give 8c (209.3 mg, 55% yield) as a white solid.

[0108] (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(3-(diphenylphosphinoyl)propyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (8c)

[0109] 8b (686mg, 1mmol) and NaN (130mg, 2mmol) are loaded into an oven-dried 25mL Schlenk flask equipped with a magnetic stirring bar. The flask is sealed with a rubber stopper, evacuated and filled with nitrogen three times. Then, DMF (10mL, 0.1M) is added by syringe. The reaction is stirred at 60 ° C for 3 hours, and crude NMR shows that 8b is completely converted. Afterwards, brine (10mL) and EA (10mL) are added, and each layer is separated. The organic phase is washed three times with brine (3×10mL), and the combined aqueous phase is extracted once with EA (10mL). The combined organic phase is dried over Na SO, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) to produce 8d (520mg, 86% yield) as a white solid.

[0110] (R)-5-(3-azidopropyl)-6-(1-benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (8d)

[0111] 8d (120.3 mg, 0.2 mmol), CuSO4 (1.6 mg, 0.01 mmol) and sodium ascorbate (7.9 mg, 0.04 mmol) were placed in a 10 mL reaction tube equipped with a magnetic stirring bar. Then, 8d (120.3 mg, 0.2 mmol) and sodium ascorbate (7.9 mg, 0.04 mmol) were added sequentially via a syringe. t BuOH (1mL), H2O (1mL) and phenylacetylene (44 μL, 0.4mmol). The tube is sealed with a rubber stopper, and the reaction is stirred at 60 ° C for 15 hours. Afterwards, TLC shows that 8d is completely converted. Add saline (10mL) and EA (10mL), and separate the layers (note: ultrasonic waves are used to ensure that all substances are dissolved in the solution). The organic phase is washed three times with saline (3×10mL), and the combined aqueous phase is extracted once with EA (10mL). The combined organic phase is dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane / EA=3 / 1-2 / 1) to produce 8e (136.5mg, 97% yield) as a white solid.

[0112] (R)-5-(1-Benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-(3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (8e)

[0113] 3.2 Synthesis of tetra-ortho-substituted axially chiral arylboron compounds

[0114] Procedure: 4a (106.5 mg, 0.2 mmol, 98% ee) was charged into an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar. The tube was sealed with a rubber stopper, evacuated and filled with nitrogen three times followed by the addition of dry THF (2 mL). Then, LiHMDS (0.4 mL, 1 M in THF) was slowly added to the mixture via syringe. The reaction was stirred at room temperature for 10 minutes and the solution turned yellow. Thereafter, an electrophile (0.5 mmol) was added to the mixture and the reaction was further stirred at room temperature for 1 hour. TLC or crude NMR showed complete conversion of 4a. The mixture was filtered through a short pad of silica gel and rinsed with EA. The filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography to yield 9a-f. See Fig.18 . (S)-5-(1-Benzyl-3-methyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9a) According to the above procedure, 9a was prepared by using iodomethane (31 μL, 0.5 mmol) as an electrophile. Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 9a (90.4 mg, 83% yield) as a white solid. (S)-5-(1-Benzyl-3-(trimethylsilyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9b) According to the above procedure, 9b was prepared by using trimethylsilyl chloride (63.4 μL, 0.5 mmol) as an electrophile. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-15 / 1) gave 9b (109.7 mg, 91% yield) as a white solid. (S)-5-(4-Benzyl-1-benzyl-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9c) According to the above procedure, 9c was prepared by using benzoyl chloride (58 μL, 0.5 mmol) as an electrophile. Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 9c (119.3 mg, 94% yield) as a yellow solid. 1 H-NMR and 13 C-DEPT 135 NMR analysis clearly showed that benzoylation occurred at the naphthalene position rather than the N position. 1 In the H-NMR spectrum, a downfield proton chemical shift (δ = 11.03) was observed due to the intramolecular hydrogen bonding between the NH and benzoyl O atoms. 13 C-DEPT 135 NMR spectroscopy showed that a total of 11 CH groups were observed in the aromatic region. (R)-5-(1-Benzyl-3-(diphenylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9d) According to the above procedure, 9d was prepared by using chlorodiphenylphosphine (90 μL, 0.5 mmol) as an electrophile. Purification by silica gel column chromatography (n-hexane / EA=8 / 1-6 / 1) gave 9d (126.1 mg, 88% yield) as a white solid. (R)-5-(1-Benzyl-3-(dicyclohexylphosphanyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9e) According to the above procedure, 9e was prepared by using chlorodicyclohexylphosphine (110.4 μL, 0.5 mmol) as an electrophile. Purification by silica gel column chromatography (n-hexane / EA=20 / 1-16 / 1) gave 9e (128.8 mg, 88% yield) as a white solid. (R)-5-(1-Benzyl-3-(diisopropylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,6,7-trimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9f) According to the above procedure, 9f was prepared by using chlorodiisopropylphosphine (80 μL, 0.5 mmol) as an electrophile. Purification by silica gel column chromatography (n-hexane / EA=15 / 1-10 / 1) gave 9f (94.4 mg, 73% yield) as a white solid.

[0115] 3.3 Construction of novel chiral phosphine ligand library

[0116] Procedure: Axial chiral arylboron scaffold 4 or 6 or 8 (0.2 mmol) was loaded into an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar. The tube was sealed with a rubber stopper, evacuated and filled with nitrogen three times, followed by the addition of dry THF (2 mL). Then, LiHMDS (0.4 mL, 1 M in THF) was slowly added to the mixture via a syringe. The reaction was stirred at room temperature for 10 minutes, and the solution turned yellow. Thereafter, phosphine electrophile Cl-PR2 (0.5 mmol) was added to the mixture and the reaction was further stirred at room temperature for 1 hour. TLC or crude NMR showed complete conversion of the substrate. The mixture was filtered through a short silica gel pad and rinsed with EA. The filtrate was concentrated under reduced pressure to produce a crude product, which was purified by silica gel column chromatography to produce chiral phosphine ligands 9g-w. See Fig.19 . (S)-5-(1-Benzyl-3-(diphenylphosphinyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-((trimethylsilyl)methyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9 g) According to the above procedure, 9g was prepared from 4o (90.7 mg, 0.15 mmol, 98% ee) and chlorodiphenylphosphine (67.3 μL, 0.375 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-8 / 1) gave 9g (104.0 mg, 88% yield) as a white solid. (S)-5-(1-benzyl-3-(dicyclohexylphosphino)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-((trimethylsilyl)methyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9h) According to the above procedure, 9h was prepared from 4o (90.7 mg, 0.15 mmol, 98% ee) and chlorodicyclohexylphosphine (83 μL, 0.375 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-16 / 1) gave 9h (69.0 mg, 57% yield) as a white solid. (S)-5-(1-Benzyl-3-(diphenylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenylethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9i) According to the above procedure, 9i was prepared from 4g (105.8 mg, 0.17 mmol, 94% ee) and chlorodiphenylphosphine (76 μL, 0.425 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1-8 / 1) gave 9i (124.7 mg, 91% yield) as a white solid. (S)-5-(1-Benzyl-3-(dicyclohexylphosphanyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenylethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9j) According to the above procedure, 9j was prepared from 4g (105.8 mg, 0.17 mmol, 94% ee) and chlorodicyclohexylphosphine (94 μL, 0.425 mmol). Purification by silica gel column chromatography (n-hexane / EA=20 / 1-10 / 1) gave 9j (111.5 mg, 80% yield) as a white solid. (S)-5-(1-Benzyl-3-(diphenylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(3-chloropropyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9k) According to the above procedure, 9k was prepared from 4h (119 mg, 0.2 mmol, 96% ee) and chlorodiphenylphosphine (90 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=6 / 1-5 / 1) gave 9k (141.9 mg, 91% yield) as a white solid. (S)-5-(1-benzyl-3-(dicyclohexylphosphanyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(3-chloropropyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9l) According to the above procedure, 91 was prepared from 4h (119 mg, 0.2 mmol, 96% ee) and chlorodicyclohexylphosphine (110.4 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=9 / 1) gave 91 (139.2 mg, 88% yield) as a white solid. (S)-5-(1-Benzyl-3-(diphenylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9m) According to the above procedure, 9m was prepared from 4i (270.7 mg, 0.4 mmol, 95% ee) and chlorodiphenylphosphine (180 μL, 1 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 9m (321.5 mg, 99% yield) as a white solid. (S)-5-(1-Benzyl-3-(diphenylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-(3-(phenylthio)propyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9n) According to the above procedure, 9n was prepared from 8a (133.7 mg, 0.2 mmol, 96% ee) and chlorodiphenylphosphine (90 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=9 / 1-5 / 1) gave 9n (152.2 mg, 89% yield) as a white solid. (S)-5-(1-benzyl-3-(dicyclohexylphosphanyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-(3-(phenylthio)propyl)-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9o) According to the above procedure, 9o was prepared from 8a (120.4 mg, 0.18 mmol, 96% ee) and chlorodicyclohexylphosphine (100 μL, 0.45 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1) gave 9o (139.1 mg, 89% yield) as a white solid. (S)-5-(1-Benzyl-3-(diphenylphosphino)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(3-(diphenylphosphino)propyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9p) (S)-5-(1-Benzyl-3-(diphenylphosphinyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9q) (S)-(E)-5-(1-Benzyl-3-(diphenylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenylvinyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9r) According to the above procedure, 9r was prepared from 4s (124.1 mg, 0.2 mmol, 93% ee) and chlorodiphenylphosphine (90 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 9r (145.3 mg, 90% yield) as a white solid. (S)-(E)-5-(1-Benzyl-3-(dicyclohexylphosphinyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-4,7-dimethyl-6-phenylvinyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9s) According to the above procedure, 9s was prepared from 4s (124.1 mg, 0.2 mmol, 93% ee) and chlorodicyclohexylphosphine (110.4 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1) gave 9s (129.8 mg, 79% yield) as a white solid. (R)-1-Benzyl-3-(diphenylphosphinoyl)-2-(4,6,7-trimethyl-2-toluenesulfonylisoindolin-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (9t) According to the above procedure, 9t was prepared from 4b (114.3 mg, 0.2 mmol, 99% ee) and chlorodiphenylphosphine (90 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 9t (144.2 mg, 95% yield) as a white solid. (R)-1-Benzyl-3-(dicyclohexylphosphanyl)-2-(4,6,7-trimethyl-2-toluenesulfonylisoindolin-5-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinyl (9u) According to the above procedure, 9u was prepared from 4b (114.3 mg, 0.2 mmol, 99% ee) and chlorodicyclohexylphosphine (110.4 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=15 / 1) gave 9u (132.8 mg, 86% yield) as a white solid. (S)-5-(3-chloropropyl)-6-(1-(diphenylphosphinoyl)-3-methyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9v) According to the above procedure, 9v was prepared from 6c (99.4 mg, 0.2 mmol, 96% ee) and chlorodiphenylphosphine (90 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=4 / 1-3 / 1) gave 9v (95.3 mg, 70% yield) as a white solid. (S)-5-(3-chloropropyl)-6-(1-(dicyclohexylphosphatyl)-3-methyl-4-oxo-3,4-dihydrobenzo[d][1,3,2]diazaborin-2(1H)-yl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9w) According to the above procedure, 9w was prepared from 6c (99.4 mg, 0.2 mmol, 96% ee) and chlorodicyclohexylphosphine (110.4 μL, 0.5 mmol). Purification by silica gel column chromatography (n-hexane / EA=5 / 1-4 / 1) gave 9w (125.4 mg, 90% yield) as a white solid.

[0117] 9p (283.5mg, 0.3mmol) is loaded into the oven-dried 10mL Schlenk tube equipped with a magnetic stirring bar. The tube is sealed with a rubber stopper, evacuated and filled three times with nitrogen, followed by the addition of dry toluene (3mL, 0.1M) and triethylamine (0.83mL, 6mmol). Then, the mixture is cooled to 0 ℃ and trichlorosilane (0.15mL, 1.5mmol) is added dropwise by a syringe. After the addition is complete, the reaction is heated to 100 ℃ and stirred for 12 hours. TLC shows that 9p is fully converted. The mixture is poured into 0 ℃ 10mL water and EA (10mL) is added. Each layer is separated, and aqueous phase is extracted three times (3 × 10mL) with EA. The combined organic phase was washed once with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) to give 9x (227.4 mg, 82% yield) as a white solid. (S)-5-(1-Benzyl-3-(diphenylphosphinoyl)-1H-naphtho[1,8-de][1,3,2]diazaborin-2(3H)-yl)-6-(3-(diphenylphosphinoyl)propyl)-4,7-dimethyl-1,3-dihydro-2H-indene-2,2-dicarboxylic acid dimethyl ester (9x)

[0118] 3.4 Synthesis of CB atropisomers

[0119]

[0136] Procedure: OT-substituted axial chiral arylboron scaffold 4j-1 (0.45 mmol) was charged into an oven-dried 25 mL Schlenk flask equipped with a magnetic stirring bar. The flask was sealed with a rubber stopper, evacuated and filled with nitrogen three times, followed by the addition of dry THF (4.5 mL, 0.1 M). Then, LiHMDS (0.9 mL, 0.1 M in THF) was slowly added to the mixture via a syringe. The reaction was stirred at room temperature for 1 hour, and TLC showed complete conversion of substrate 4j-1. The mixture was filtered through a short pad of silica gel and rinsed with EA. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give bridged CB atropisomers 11a-c. See Fig. 20 .

[0120] 13-Benzyl-7,11-dimethyl-5,6,8,10-tetrahydro-9H,13H-indeno[5',6':3,4][1,2]azaborano[1,2-a]naphtho[1,8-de][1,3,2]diazaborano-9,9-dicarboxylic acid dimethyl ester (11a)

[0121] According to the above procedure, 11a was prepared from 4j (322.5 mg, 0.45 mmol, 94% ee). Purification by silica gel column chromatography (n-hexane / EA=5 / 1) gave 11a (159.8 mg, 65% yield) as a white solid. The HPLC trace showed that 11a was unstable in configuration and may undergo racemization at room temperature.

[0122] (R)-14-Benzyl-8,12-dimethyl-6,7,9,11-tetrahydro-14H-indeno[5,6-c]naphtho[1',8':4,5,6][1,3,2]diazaborolino[1,2-a][1,2]azaborolino[10,10(5H)-dicarboxylic acid dimethyl ester (11b)

[0123] According to the above procedure, 11b was prepared from 4k (321.5 mg, 0.44 mmol, 94% ee). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 11b (133.3 mg, 54% yield) as a white solid.

[0124] (R)-15-Benzyl-9,13-dimethyl-5,6,7,8,10,12-hexahydro-11H,15H-indeno[5,6-c]naphtho[1',8':4,5,6][1,3,2]diazaborolino[1,2-a][1,2]azaboroctane-11,11-dicarboxylic acid dimethyl ester (11c)

[0125] According to the above procedure, 11c was prepared from 41 (327.7 mg, 0.44 mmol, 93% ee). Purification by silica gel column chromatography (n-hexane / EA=10 / 1-5 / 1) gave 11c (140.2 mg, 56% yield) as a white solid.

[0126] 4. Application of newly synthesized chiral ligands in asymmetric catalysis

[0127] 4.1 Application in Pd-catalyzed asymmetric allylic alkylation

[0128] Procedure: [Pd(allyl)Cl]2 (0.9 mg, 2.5 mol%), chiral ligand (5 mol%) and KOAc (2.0 mg, 0.02 mmol) were loaded into an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar. The tube was sealed with a rubber stopper, evacuated and filled with nitrogen three times. Then, dry DCM (1 mL), BSA (73 μL, 0.3 mmol), 10b (46 μL, 0.3 mmol) and 10a (24 μL, 0.1 mmol) were added sequentially by syringe. The reaction was stirred at room temperature for 48 hours. Afterwards, the mixture was filtered through a short silica gel pad and rinsed with EA. The filtrate was concentrated under reduced pressure. The residue was dissolved in CDCl3 and CH2Br2 (7 μL, 0.1 mmol) was added as an internal standard. 1 H-NMR analysis gave the yield of 10c. The crude product was purified by preparative thin layer chromatography to produce pure 10c. The ee value of 10c was determined by chiral HPLC. Conditions: IA-3, n-hexane / IPA=92 / 8, 1.0 ml / min, 220 nm, tr=7.922 min (major), 9.822 min (minor). By comparing the HPLC traces reported in the literature, the absolute configuration of the major enantiomer was assigned to the R configuration.

[0129] Table 1 below shows the yield and enantiomeric excess of the novel chiral phosphine ligand-assisted Pd-catalyzed asymmetric allylic alkylation in the present invention.

[0130] Table 1: a CH2Br2 was used as an internal standard by 1 Yield determined by H-NMR b Determination of ee by chiral HPLC

[0131] 4.2 Application in Pd-catalyzed asymmetric Suzuki coupling

[0132] Procedure: Pd2(dba)3 (2.3 mg, 2.5 mol%), chiral ligand (6 mol%), K2CO3 (41.5 mg, 0.3 mmol), 10d (23.7 mg, 0.1 mmol), 10e (34.4 mg, 0.2 mmol) were loaded into an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar. The tube was sealed with a rubber stopper, evacuated and filled with nitrogen three times. Toluene (1 mL) and H2O (0.2 mL) were then added sequentially via a syringe. The reaction was stirred at 60°C for 24 hours. Afterwards, the reaction was cooled to room temperature and brine (5 mL) and EA (5 mL) were added. The layers were separated and the aqueous phase was extracted three times with EA (3×5 mL). The combined organic phases were washed once with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in CDCl3 and CH2Br2 (7 μL, 0.1 mmol) was added as an internal standard. 1 H-NMR analysis gave the yield of 10f. The crude product was purified by preparative thin layer chromatography to produce pure 10f. The ee value of 10f was determined by chiral HPLC. Conditions: IA-3, n-hexane / IPA=99 / 1, 1.0 ml / min, 220 nm, tr=4.903 min (minor), 5.837 min (major). By comparing the HPLC traces reported in the literature, the absolute configuration of the major enantiomer was assigned to the S configuration.

[0133] Table 2 below shows the yield and enantiomeric excess of the novel chiral phosphine ligand-assisted Pd-catalyzed asymmetric Suzuki coupling of the present invention.

[0134] Table 2: a CH2Br2 was used as an internal standard by 1 Yield determined by H-NMR b Determination of ee by chiral HPLC

[0135] The above description of the present invention has been provided for the purpose of illustration and description. It is not intended to be exhaustive or to limit the present invention to the precise form disclosed. For those skilled in the art, many modifications and variations will be apparent.

[0136] The embodiments were chosen and described in order to best explain the principles of the invention and its practical application, thereby enabling others skilled in the art to understand the invention for various embodiments and with various modifications as are suited to the particular use contemplated.

Claims

1. A compound represented by the following formula: Wherein R is selected from phenyl or cyclohexyl; wherein X is selected from N-toluenesulfonyl, wherein R1 is selected from substituted or unsubstituted (C 1-4 ) alkyl, benzyl Wherein R2 is selected from methyl or ethyl; wherein R3 is selected from substituted or unsubstituted (C 1-5 ) alkyl, substituted or unsubstituted (C 1-5 )alkenyl, phenyl or cyclopropane; and Where Y is selected from 2. The compound according to claim 1, which is represented by the following formula: Wherein R is selected from phenyl or cyclohexyl.

3. A method for preparing the compound according to claim 1, the method comprising: An axially chiral organoboron compound represented by the following formula was prepared: wherein R1 is selected from substituted or unsubstituted (C 1-4 ) alkyl, benzyl, R2 is selected from methyl or ethyl; R3 is selected from substituted or unsubstituted (C 1-5 ) alkyl, substituted or unsubstituted (C 1-5 )alkenyl, phenyl or cyclopropane; and Y is selected from reacting the axial chiral organoboron compound with lithium bis(trimethylsilyl)amide (LiHDMS) in the presence of tetrahydrofuran at room temperature for 8-12 minutes to obtain an intermediate; The intermediate is reacted with a phosphine chloride having the formula Cl-PR2, wherein R is selected from phenyl or cyclohexyl, at room temperature for 1 hour.

4. The method of claim 3, wherein the method has a yield of at least 70%.

5. The process according to claim 3, wherein the enantiomeric excess of the compound according to claim 1 obtained is at least 90%.

6. An improvement in a method for synthesizing an axially chiral aromatic organoboron compound, wherein the improvement comprises reacting a boron-containing organic precursor material and a branched linear organic precursor material in the presence of a rhodium catalyst and a chiral ligand.

7. The improvement of claim 6, wherein said reacting said boron-containing organic precursor material and branched linear organic precursor material in the presence of a rhodium catalyst and a chiral ligand is carried out in an organic solvent at 55°C to 65°C for about 20 hours.

8. The improvement of claim 6, wherein the branched linear organic precursor material is a diyne represented by the formula: Wherein R2 is selected from methyl or ethyl.

9. The improvement of claim 6, wherein the linear boron-containing organic precursor material is an alkynyl boron compound represented by the formula: wherein R1 is selected from substituted or unsubstituted (C 1-4 ) alkyl, benzyl wherein R3 is selected from substituted or unsubstituted (C 1-5 ) alkyl, substituted or unsubstituted (C 1-5 )alkenyl, phenyl or cyclopropane; and Where Y is selected from 10. The improvement of claim 6 wherein the improved process has a yield of at least 50%.

11. The improvement of claim 6 wherein the axially chiral aromatic organoboron compound has an enantiomeric excess of at least 85%.

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